Therapeutic compounds and uses thereof

ABSTRACT

The present invention relates to compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     and to salts thereof, wherein R 1 , R 2 , R c , and R d  have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of bromodomains. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various bromodomain-mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority of U.S.application Ser. No. 62/077,711, filed Nov. 10, 2014, which applicationis herein incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofbromodomains.

BACKGROUND OF THE INVENTION

Chromatin is a complex combination of DNA and protein that makes upchromosomes. It is found inside the nuclei of eukaryotic cells and isdivided between heterochromatin (condensed) and euchromatin (extended)forms. The major components of chromatin are DNA and proteins. Histonesare the chief protein components of chromatin, acting as spools aroundwhich DNA winds. The functions of chromatin are to package DNA into asmaller volume to fit in the cell, to strengthen the DNA to allowmitosis and meiosis, and to serve as a mechanism to control expressionand DNA replication. The chromatin structure is controlled by a seriesof post-translational modifications to histone proteins, notablyhistones H3 and H4, and most commonly within the “histone tails” whichextend beyond the core nucleosome structure. Histone tails tend to befree for protein-protein interaction and are also the portion of thehistone most prone to post-translational modification. Thesemodifications include acetylation, methylation, phosphorylation,ubiquitinylation, and SUMOylation. These epigenetic marks are writtenand erased by specific enzymes that place the tags on specific residueswithin the histone tail, thereby forming an epigenetic code, which isthen interpreted by the cell to allow gene specific regulation ofchromatin structure and thereby transcription.

Of all classes of proteins, histones are amongst the most susceptible topost-translational modification. Histone modifications are dynamic, asthey can be added or removed in response to specific stimuli, and thesemodifications direct both structural changes to chromatin andalterations in gene transcription. Distinct classes of enzymes, namelyhistone acetyltransferases (HATs) and histone deacetylases (HDACs),acetylate or de-acetylate specific histone lysine residues (Struhl K.,Genes Dev., 1989, 12, 5, 599-606).

Bromodomains, which are approximately 110 amino acids long, are found ina large number of chromatin-associated proteins and have been identifiedin approximately 70 human proteins, often adjacent to other proteinmotifs (Jeanmougin F., et al., Trends Biochem. Sci., 1997, 22, 5,151-153; and Tamkun J. W., et al., Cell, 1992, 7, 3, 561-572).Interactions between bromodomains and modified histones may be animportant mechanism underlying chromatin structural changes and generegulation. Bromodomain-containing proteins have been implicated indisease processes including cancer, inflammation and viral replication.See, e.g., Prinjha et al., Trends Pharm. Sci., 33(3):146-153 (2012) andMuller et al., Expert Rev., 13(29):1-20 (September 2011).

Cell-type specificity and proper tissue functionality requires the tightcontrol of distinct transcriptional programs that are intimatelyinfluenced by their environment. Alterations to this transcriptionalhomeostasis are directly associated with numerous disease states, mostnotably cancer, immuno-inflammation, neurological disorders, andmetabolic diseases. Bromodomains reside within key chromatin modifyingcomplexes that serve to control distinctive disease-associatedtranscriptional pathways. This is highlighted by the observation thatmutations in bromodomain-containing proteins are linked to cancer, aswell as immune and neurologic dysfunction. Moreover, recent findingshave demonstrated that small molecule inhibition of the bromodomains ofBRD4 may have clinical utility in diverse human diseases, ranging fromauto-immunity to cardiac hypertrophy. This is possible because theunderlying mechanism resides in transcriptional regulation. Hence, theselective inhibition of bromodomains across the family creates variedopportunities as novel therapeutic agents in human dysfunction.

There is a need for treatments for cancer, immunological disorders, andother bromodomain related diseases.

SUMMARY OF THE INVENTION

One aspect includes a compound of formula (I):

or a salt thereof, wherein:

R¹ is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or carbocyclyl, whereineach C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and carbocyclyl of R¹ isoptionally substituted with one or more groups R^(a);

R² is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or C₃₋₈cycloalkyl,wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and C₃₋₈cycloalkylof R² is optionally substituted with one or more groups R^(b); and

each R^(a) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂,—S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —O—C(O)—O—R^(v),—C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂,—N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v),—N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl, is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN,—C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v),—O—C(O)—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v),—N(R^(v))—S(O)₂—R^(v) and C₁₋₆alkyl that is optionally substituted withone or more groups independently selected from oxo and halo;

each R^(b) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂,—S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w),—C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂,—N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w),—N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(w))₂, —CN,—C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w),—O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w),—N(R^(w))—S(O)₂—R^(w) and C₁₋₆alkyl that is optionally substituted withone or more groups independently selected from oxo and halo;

each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more substituent groups independentlyselected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups, is optionally substituted with one or moregroups independently selected from oxo, carbocyclyl, heterocyclyl, halo,—NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionallysubstituted with one or more groups independently selected from oxo,halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that isoptionally substituted with one or more groups independently selectedfrom halo, and C₁₋₆alkyl;

or R^(c) and R^(d) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))C(O)OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂,and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more groupsindependently selected from halo and C₁₋₆alkyl;

each R^(h) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groupsindependently selected from oxo and halo; or two R^(h) are takentogether with the nitrogen to which they are attached to form aheterocyclyl that is optionally substituted with one or more groupsindependently selected from oxo, halo and C₁₋₃alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo;

each R^(v) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, and C₁-C₆alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or two R^(v) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo; and

each R^(w) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or two R^(w) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo.

Another aspect includes a composition comprising a compound of formula(I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable adjuvant, carrier, or vehicle.

Another aspect includes a method for treating a bromodomain-mediateddisorder in an animal (e.g., a mammal such as a human) comprisingadministering a compound of formula (I) or a pharmaceutically acceptablesalt thereof to the animal.

Another aspect includes a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for use in medical therapy.

Another aspect includes a compound of formula (I) or a pharmaceuticallyacceptable salt thereof for the prophylactic or therapeutic treatment ofa bromodomain-mediated disorder.

Another aspect includes the use of a compound of formula (I) or apharmaceutically acceptable salt thereof to prepare a medicament fortreating a bromodomain-mediated disorder in an animal (e.g., a mammalsuch as a human).

Another aspect includes compounds for the study of bromodomains.

Another aspect includes synthetic intermediates and synthetic processesdisclosed herein that are useful for preparing a compound of formula (I)or a salt thereof.

DETAILED DESCRIPTION Compounds and Definitions

Definitions and terms are described in more detail below. Chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.

Unless otherwise stated, compounds of formula I include enantiomeric,diastereomeric and geometric (or conformational) isomeric forms of agiven structure. For example, the R and S configurations for eachasymmetric center, Z and E double bond isomers, Z and E conformationalisomers, single stereochemical isomers, as well as enantiomeric,diastereomeric, and geometric (or conformational) mixtures are included.Unless otherwise stated, all tautomeric forms of structures depictedherein are included. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds of formula I, wherein the independent replacement orenrichment of one or more hydrogen by deuterium or tritium, carbon by¹³C- or ¹⁴C carbon, nitrogen by a ¹⁵N nitrogen, sulfur by a ³³S, ³⁴S or³⁶S sulfur, or oxygen by a ¹⁷O or ¹⁸O oxygen are included. Suchcompounds are useful, for example, as analytical tools, as probes inbiological assays, or as therapeutic agents.

Where a particular enantiomer is described, it may, in certainembodiments be provided substantially free of the correspondingenantiomer, and may also be referred to as “optically enriched.”“Optically-enriched,” as used herein, means that the mixture ofenantiomers is made up of a significantly greater proportion of oneenantiomer, and may be described by enantiomeric excess (ee %). Incertain embodiments, the mixture of enantiomers is made up of at leastabout 90% by weight of a given enantiomer (about 90% ee). In otherembodiments, the mixture of enantiomers is made up of at least about95%, 98% or 99% by weight of a given enantiomer (about 95%, 98% or 99%ee). Enantiomers and diastereomers may be isolated from racemic mixturesby any method known to those skilled in the art, includingrecrystallization from solvents in which one stereoisomer is moresoluble than the other, chiral high pressure liquid chromatography(HPLC), supercritical fluid chromatography (SFC), the formation andcrystallization of chiral salts, which are then separated by any of theabove methods, or prepared by asymmetric syntheses and optionallyfurther enriched. See, for example, Jacques et al., Enantiomers,Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen,et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry ofCarbon Compounds (McGraw-Hill, N Y, 1962); Wilen, S. H. Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972).

The term “heteroatom” means any atom independently selected from an atomother than carbon or hydrogen, for example, one or more of oxygen,sulfur, nitrogen, phosphorus or silicon (including any oxidized form ofnitrogen, sulfur, phosphorus or silicon; and the quaternized form of anynitrogen).

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br)and iodine (iodo, —I).

The term “oxo” refers to ═O or (═O)₂.

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “carbocyclyl” used alone or as part of a larger moiety, refersto a saturated, partially unsaturated, or aromatic ring system having 3to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12carbon atoms (C₃-C₁₂). In another embodiment, carbocyclyl includesC₃-C₈, C₃-C₁₀ or C₅-C₁₀. In other embodiment, carbocyclyl, as amonocycle, includes C₃-C₈, C₃-C₆ or C₅-C₆. In another embodiment,carbocyclyl, as a bicycle, includes C₇-C₁₂. In another embodiment,carbocyclyl, as a spiro system, includes C₅-C₁₂. Examples of monocycliccarbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicycliccarbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5],[5,5], [5,6] or [6,6] ring systems, for example bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane; and spirocarbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane,spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.

The term carbocyclyl includes aryl ring systems as defined herein. Theterm carbocycyl also includes cycloalkyl rings (e.g. saturated orpartially unsaturated mono-, bi-, or spiro-carbocycles).

The term “alkyl,” as used herein, refers to a saturated linear orbranched-chain monovalent hydrocarbon radical. In one embodiment, thealkyl radical is one to eighteen carbon atoms (C₁-C₁₈). In otherembodiments, the alkyl radical is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀,C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄ or C₁-C₃. C₀ alkyl refers to a bond. Examplesof alkyl groups include methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu,i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, heptyl, octyl, nonyl, decyl,undecyl and dodecyl.

The term “alkenyl,” as used herein, denotes a linear or branched-chainmonovalent hydrocarbon radical with at least one carbon-carbon doublebond. An alkenyl includes radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. In oneexample, the alkenyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethenyl or vinyl(—CH═CH₂), prop-1-enyl (—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂),2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl,hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

The term “alkynyl,” as used herein, refers to a linear or branchedmonovalent hydrocarbon radical with at least one carbon-carbon triplebond. In one example, the alkynyl radical is two to eighteen carbonatoms (C₂-C₁₈). In other examples, the alkynyl radical is C₂-C₁₂,C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Examples include, but are not limited to,ethynyl (—C≡CH), prop-1-ynyl (—C≡CCH₃), prop-2-ynyl (propargyl,—CH₂C≡CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

The term “alkoxy” refers to a linear or branched monovalent radicalrepresented by the formula —OR in which R is alkyl, alkenyl, alkynyl orcarbocycyl. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,and cyclopropoxy.

The term “haloalkyl,” as used herein, refers to an alkyl as definedherein that is substituted with one or more (e.g. 1, 2, 3, or 4) halogroups.

The term “aryl” used alone or as part of a larger moiety as in“arylalkyl”, “arylalkoxy”, or “aryloxyalkyl”, refers to a monocyclic,bicyclic or tricyclic, carbon ring system, that includes fused rings,wherein at least one ring in the system is aromatic. The term “aryl” maybe used interchangeably with the term “aryl ring”. In one embodiment,aryl includes groups having 6-18 carbon atoms. In another embodiment,aryl includes groups having 6-10 carbon atoms. Examples of aryl groupsinclude phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl,naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl,2,3-dihydro-1H-indenyl, and the like, which may be substituted orindependently substituted by one or more substituents described herein.A particular aryl is phenyl. In another embodiment aryl includes an arylring fused to one or more carbocyclic rings, such as indanyl,naphthimidyl, or tetrahydronaphthyl, and the like, where the radical orpoint of attachment is on an aromatic ring.

The term “heteroaryl” used alone or as part of a larger moiety, e.g.,“heteroarylalkyl”, or “heteroarylalkoxy”, refers to a monocyclic,bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein atleast one ring is aromatic and contains at least one heteroatom. In oneembodiment, heteroaryl includes 4-6 membered monocyclic aromatic groupswhere one or more ring atoms is nitrogen, sulfur or oxygen that isindependently optionally substituted. In another embodiment, heteroarylincludes 5-6 membered monocyclic aromatic groups where one or more ringatoms is nitrogen, sulfur or oxygen that is independently optionallysubstituted. Example heteroaryl groups include thienyl, furyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl,oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl,purinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl, benzoimidazolyl, indolyl, 1,3-thiazol-2-yl,1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl,1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl,1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The terms “heteroaryl” alsoincludes groups in which a heteroaryl is fused to one or more aryl,carbocyclyl, or heterocyclyl rings, where the radical or point ofattachment is on the heteroaryl ring. Nonlimiting examples includeindolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-, bi-or tri-cyclic.

As used herein, the term “heterocyclyl” refers to a “carbocyclyl” asdefined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atomshave been replaced with a heteroatom (e.g. O, N, or S). In someembodiments, a heterocyclyl refers to a saturated ring system, such as a3 to 12 membered saturated heterocyclyl ring system. In someembodiments, a heterocyclyl refers to a heteroaryl ring system, such asa 5 to 14 membered heteroaryl ring system. A heterocyclyl can optionallybe substituted with one or more substituents independently selected fromthose defined herein.

In one example, heterocyclyl includes 3-12 ring atoms and includesmonocycles, bicycles, tricycles and spiro ring systems, wherein the ringatoms are carbon, and one to five ring atoms is a heteroatom selectedfrom nitrogen, sulfur or oxygen, which is independently optionallysubstituted by one or more groups. In one example, heterocyclyl includes1 to 4 heteroatoms. In another example, heterocyclyl includes 3- to7-membered monocycles having one or more heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4-to 6-membered monocycles having one or more heteroatoms selected fromnitrogen, sulfur or oxygen. In another example, heterocyclyl includes3-membered monocycles. In another example, heterocyclyl includes4-membered monocycles. In another example, heterocyclyl includes 5-6membered monocycles. In one example, the heterocyclyl group includes 0to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally beoxidized (e.g. NO, SO, SO₂), and any nitrogen heteroatom may optionallybe quaternized (e.g. [NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). Example heterocyclylsinclude oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl,thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl,azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclylscontaining a sulfur or oxygen atom and one to three nitrogen atoms arethiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide,thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl,oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ringheterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl, suchas imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocyclyls arebenzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example6-membered heterocyclyls contain one to three nitrogen atoms andoptionally a sulfur or oxygen atom, for example pyridyl, such aspyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yland pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, andpyrazinyl. The pyridine N-oxides and pyridazine N-oxides and thepyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the1,3,4-triazin-2-yl groups, are other example heterocyclyl groups.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms butthe ring moiety is not aromatic.

As used herein, the term “inhibitor” refers to a compound that binds toand inhibits a bromodomain with measurable affinity and activity. Incertain embodiments, an inhibitor has an IC₅₀ or binding constant ofless about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, refer to a measurable reduction in activity of a bromodomainbetween: (i) a sample comprising a compound of formula I or compositionthereof and such bromodomain, and (ii) an equivalent sample comprisingsuch bromodomain, in the absence of said compound, or compositionthereof.

“Pharmaceutically acceptable salts” include both acid and base additionsalts. It is to be understood that when a compound or Example herein isshown as a specific salt, the corresponding free-base, as well as othersalts of the corresponding free-base (including pharmaceuticallyacceptable salts of the corresponding free-base) are contemplated.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases and which are not biologically or otherwise undesirable, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like,and organic acids may be selected from aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids such as formic acid, acetic acid, propionic acid, glycolicacid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid,citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilicacid, benzoic acid, cinnamic acid, mandelic acid, embonic acid,phenylacetic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and thelike.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases includes salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases are isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the present invention. Examples of solventsinclude water, isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid and ethanolamine. The term “hydrate” refers to the complexwhere the solvent molecule is water.

“Therapeutically effective amount” refers to an amount of a compound ofthe present invention that (i) treats the particular disease, conditionor disorder, (ii) attenuates, ameliorates or eliminates one or moresymptoms of the particular disease, condition, or disorder, or (iii)prevents or delays the onset of one or more symptoms of the particulardisease, condition or disorder described herein. In the case of cancer,the therapeutically effective amount of the drug may reduce the numberof cancer cells; reduce the tumor size; inhibit (i.e., slow to someextent and preferably stop) cancer cell infiltration into peripheralorgans; inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; inhibit, to some extent, tumor growth; and/or relieve tosome extent one or more of the symptoms associated with the cancer. Forcancer therapy, efficacy can, for example, be measured by assessing thetime to disease progression (TTP) and/or determining the response rate(RR). In the case of immunological disorders, the therapeutic effectiveamount is an amount sufficient to decrease or alleviate an allergicdisorder, the symptoms of an autoimmune and/or inflammatory disease, orthe symptoms of an acute inflammatory reaction (e.g. asthma). In someembodiments, a therapeutically effective amount is an amount of achemical entity described herein sufficient to significantly decreasethe activity or number of drug tolerant or drug tolerant persistingcancer cells.

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include one or more of preventing occurrence orrecurrence of disease, alleviation of symptoms, diminishment of anydirect or indirect pathological consequences of the disease, stabilized(i.e., not worsening) state of disease, preventing metastasis,decreasing the rate of disease progression, amelioration or palliationof the disease state, prolonging survival as compared to expectedsurvival if not receiving treatment and remission or improved prognosis.In certain embodiments, a compound of formula I is used to delaydevelopment of a disease or disorder or to slow the progression of adisease or disorder. Those individuals in need of treatment includethose already with the condition or disorder as well as those prone tohave the condition or disorder, (for example, through a genetic mutationor aberrant expression of a gene or protein) or those in which thecondition or disorder is to be prevented.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise.

As used herein, “another” means at least a second or more.

Exemplary Values

It is to be understood that two or more of the following embodiments maybe combined.

One embodiment provides a compound of formula I or a salt thereof,wherein:

R¹ is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or carbocyclyl, whereineach C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and carbocyclyl of R¹ isoptionally substituted with one or more groups R^(a);

R² is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or C₃₋₈cycloalkyl,wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and C₃₋₈cycloalkylof R² is optionally substituted with one or more groups R^(b); and

each R^(a) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂,—S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —O—C(O)—O—R^(v),—C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂,—N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v),—N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl, is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN,—C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v),—O—C(O)—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v),—N(R^(v))—S(O)₂—R^(v) and C₁₋₆alkyl that is optionally substituted withone or more groups independently selected from oxo and halo;

each R^(b) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂,—S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w),—C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂,—N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w),—N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(w))₂—CN,—C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w),—O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—C(O) N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w),—N(R^(w))—S(O)₂—R^(w) and C₁₋₆alkyl that is optionally substituted withone or more groups independently selected from oxo and halo;

each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more substituent groups independentlyselected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —C, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups, is optionally substituted with one or moregroups independently selected from oxo, carbocyclyl, heterocyclyl, halo,—NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionallysubstituted with one or more groups independently selected from oxo,halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that isoptionally substituted with one or more groups independently selectedfrom halo, and C₁₋₆alkyl;

or R^(c) and R^(d) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O) OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂O—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂,—N(R^(h))—C(O)OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂,and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more groupsindependently selected from halo and C₁₋₆alkyl;

each R^(h) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groupsindependently selected from oxo and halo; or two R^(h) are takentogether with the nitrogen to which they are attached to form aheterocyclyl that is optionally substituted with one or more groupsindependently selected from oxo, halo and C₁₋₃alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo;

each R^(v) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or two R^(v) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo; and

each R^(w) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or two R^(w) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo.

One embodiment provides a compound of formula I or a salt thereof,wherein:

R¹ is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or carbocyclyl, whereineach C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and carbocyclyl of R¹ isoptionally substituted with one or more groups R^(a);

R² is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, or C₃₋₈cycloalkyl,wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl, and C₃₋₈cycloalkylof R² is optionally substituted with one or more groups R^(b); and

each R^(a) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂,—S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v), —O—C(O)—O—R^(v),—C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂,—N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v),—N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl, is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN,—C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v),—O—C(O)—R^(v), —C(O)R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v),—N(R^(v))—S(O)₂—R^(v) and C₁₋₆alkyl that is optionally substituted withone or more groups independently selected from oxo and halo;

each R^(b) is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂,—S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w),—C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—O—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂,—N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w),—N(R^(w))—S(O)—N(R^(w))₂, and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(w))₂, —CN,—C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w),—O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w),—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w),—N(R^(w))—S(O)₂—R^(w) and C₁₋₆alkyl that is optionally substituted withone or more groups independently selected from oxo and halo;

each R^(c) and R^(d) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more substituent groups independentlyselected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl of the substituent groups, is optionally substituted withone or more groups independently selected from oxo, carbocyclyl,heterocyclyl, halo, —NO₂, —N(R^(h))₂—CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂—O—R^(h), —S—R^(h), —O—C(O)—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substitutedwith one or more groups independently selected from oxo, halo,C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that isoptionally substituted with one or more groups independently selectedfrom halo, and C₁₋₆alkyl;

or R^(c) and R^(d) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I,—NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h)),—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂,and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆₆alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more groupsindependently selected from halo and C₁₋₆alkyl;

each R^(h) is independently selected from hydrogen, C₁₋₆₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, carbocyclyl, heterocyclyl, and C₁-C₆alkyl that is optionally substituted with one or more groupsindependently selected from oxo and halo; or two R^(h) are takentogether with the nitrogen to which they are attached to form aheterocyclyl that is optionally substituted with one or more groupsindependently selected from oxo, halo and C₁₋₃alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo;

each R^(v) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or two R^(v) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo; and

each R^(w) is independently selected from hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein eachC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo; or two R^(w) are taken together with the nitrogen to which theyare attached to form a heterocyclyl that is optionally substituted withone or more groups independently selected from oxo, halo and C₁₋₃alkylthat is optionally substituted with one or more groups independentlyselected from oxo and halo.

In certain embodiments R¹ is C₁₋₁₂alkyl or C₂₋₁₂alkenyl, wherein eachC₁₋₁₂alkyl and C₂₋₁₂alkenyl is optionally substituted with one or moregroups R^(a).

In certain embodiments R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein eachC₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or moregroups R^(a).

In certain embodiments R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein eachC₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or moregroups independently selected from carbocyclyl, heterocyclyl, —F, —Cl,—Br, —I, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂, —O—R^(v), —O—C(O)—R^(v),—C(O)—R^(v), and —C(O)—O—R^(v).

In certain embodiments R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein eachC₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or moregroups independently selected from carbocyclyl, —F, —Cl, —O—R^(v),—O—C(O)—R^(v), —C(O)—R^(v), and —C(O)—O—R^(v).

In certain embodiments R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein eachC₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or moregroups independently selected from C₃₋₆cycloalkyl.

In certain embodiments R¹ is methyl, butyl, 2-propenyl, 2-buten-1-yl,3-buten-1-yl or 2-cyclopropylethyl.

In certain embodiments R² is H or C₁₋₁₂alkyl wherein each C₁₋₁₂alkyl isoptionally substituted with one or more groups R^(b).

In certain embodiments R² is H or C₁₋₆alkyl wherein each C₁₋₁₂alkyl isoptionally substituted with one or more groups R^(b).

In certain embodiments R² is H or C₁₋₆alkyl wherein each C₁₋₁₂alkyl isoptionally substituted with one or more carbocyclyl, —F, —Cl, —O—R^(w),—O—C(O)—R^(w), —C(O)—R^(w), —C(O)—O—R^(w).

In certain embodiments R² is H or methyl.

In certain embodiments R² is H.

In certain embodiments R^(c) is hydrogen, C₁₋₆alkyl, or carbocyclyl,wherein each C₁₋₆alkyl and carbocyclyl is optionally substituted withone or more substituent groups independently selected from oxo,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl,—Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h)) —C(O) N(R^(h)),—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups, is optionally substituted with one or moregroups independently selected from oxo, carbocyclyl, heterocyclyl, halo,—NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionallysubstituted with one or more groups independently selected from oxo,halo, C₁₋₆alkyl cyano, —O—R^(h), heterocyclyl, and carbocyclyl that isoptionally substituted with one or more groups independently selectedfrom halo and C₁₋₆alkyl.

In certain embodiments R^(c) is hydrogen, C₁₋₆alkyl, or carbocyclyl,wherein each C₁₋₆alkyl and carbocyclyl is optionally substituted withone or more substituent groups independently selected from oxo,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl,—Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl of the substituent groups is optionally substituted withone or more groups independently selected from oxo, carbocyclyl,heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substitutedwith one or more groups independently selected from oxo, halo,C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that isoptionally substituted with one or more groups independently selectedfrom halo and C₁₋₆alkyl.

In certain embodiments R^(c) is hydrogen, C₁₋₆alkyl, or C₃₋₈cycloalkyl,wherein each C₁₋₆alkyl and C₃₋₈cycloalkyl is optionally substituted withone or more substituent groups independently selected from —O—R^(h).

In certain embodiments R^(c) is hydrogen, methyl, ethyl, cyclopropyl,cyclobutyl, or 2-methoxyethyl.

In certain embodiments R^(c) is hydrogen.

In certain embodiments R^(c) is methyl, ethyl, cyclopropyl, cyclobutyl,or 2-methoxyethyl.

In certain embodiments R^(d) is C₁₋₆alkyl, carbocyclyl or heterocyclyl,wherein each C₁₋₆alkyl, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h)) C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups is optionally substituted with one or more groupsindependently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h),—S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, whichheterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted withone or more groups independently selected from oxo, halo, C₁₋₆alkyl,cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionallysubstituted with one or more groups independently selected from halo andC₁₋₆alkyl.

In certain embodiments R^(d) is C₁₋₆alkyl, carbocyclyl or heterocyclyl,wherein each C₁₋₆alkyl, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl of the substituent groups is optionally substituted withone or more groups independently selected from oxo, carbocyclyl,heterocyclyl, halo, —NO₂, —N(R^(h)), —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—C(O)—R^(h), —C(O)O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substitutedwith one or more groups independently selected from oxo, halo, cyano,—O—R^(h), heterocyclyl, and carbocyclyl that is optionally substitutedwith one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is C₁₋₆alkyl that is optionally substitutedwith one or more substituent groups independently selected from oxo,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl,—Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, and heterocyclyl of the substituentgroups is optionally substituted with one or more groups independentlyselected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂,—CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h),—S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h),—S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl,carbocyclyl and C₁₋₆alkyl are optionally substituted with one or moregroups independently selected from oxo, halo, C₁₋₆alkyl, cyano,—O—R^(h), heterocyclyl, and carbocyclyl that is optionally substitutedwith one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is C₁₋₆alkyl that is optionally substitutedwith one or more substituent groups independently selected from oxo,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl,—Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h)), and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl of the substituent groups is optionally substituted withone or more groups independently selected from oxo, carbocyclyl,heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substitutedwith one or more groups independently selected from oxo, halo, cyano,—O—R^(h), heterocyclyl, and carbocyclyl that is optionally substitutedwith one or more groups independently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(d) is carbocyclyl that is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups is optionally substituted with one or more groupsindependently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h),—S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h)), —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, whichheterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted withone or more groups independently selected from oxo, halo, C₁₋₆alkyl,cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionallysubstituted with one or more groups independently selected from halo andC₁₋₆alkyl.

In certain embodiments R^(d) is carbocyclyl that is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl of the substituent groups is optionally substituted withone or more groups independently selected from oxo, carbocyclyl,heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substitutedwith one or more groups independently selected from oxo, halo,C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that isoptionally substituted with one or more groups independently selectedfrom halo and C₁₋₆alkyl.

In certain embodiments R^(d) is heterocyclyl that is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h)) C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups is optionally substituted with one or more groupsindependently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h),—S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, whichheterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted withone or more groups independently selected from oxo, halo, C₁₋₆alkyl,cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionallysubstituted with one or more groups independently selected from halo andC₁₋₆alkyl.

In certain embodiments R^(d) is heterocyclyl that is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R², —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)R^(h), —N(R^(h)) S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl of the substituent groups is optionally substituted withone or more groups independently selected from oxo, carbocyclyl,heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h)), —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which carbocyclyl and C₁₋₆alkyl are optionally substitutedwith one or more groups independently selected from oxo, halo,C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that isoptionally substituted with one or more groups independently selectedfrom halo and C₁₋₆alkyl.

In certain embodiments R^(c) and R^(d) are taken together with thenitrogen to which they are attached to form a heterocyclyl that isoptionally substituted with one or more groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂,and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more groupsindependently selected from halo and C₁₋₆alkyl.

In certain embodiments R^(c) and R^(d) are taken together with thenitrogen to which they are attached to form a 5-6 membered monocyclicheterocyclyl or a 8-12 membered bicyclic heterocyclyl, wherein themonocyclic or bicyclic heterocyclyl is optionally substituted with oneor more groups independently selected from oxo, C₁₋₆₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂,—N(R^(v))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂,and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionally substitutedwith one or more groups independently selected from C₁₋₆alkyl,carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(h))₂, —CN,—C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h),—O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h),—S(O)₂—R^(h), —O—C(O)—N(R^(h)), —N(R^(h))—C(O)—OR^(h),—N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h),—N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and—N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more groupsindependently selected from halo and C₁₋₆alkyl.

In certain embodiments the compound is a compound as described in theExamples herein, or a freebase or salt thereof.

In certain embodiments —C(═O)NR^(c)R^(d) is selected from:

In certain embodiments —C(═O)NR^(c)R^(d) is selected from:

In certain embodiments the compound is selected from:

and salts thereof.

In certain embodiments the compound is selected from:

and salts thereof.

In certain embodiments the invention provides compound 1000 as describedin Examples 292 and 294, and salts thereof. The invention also providesa method for evaluating a compound's ability to inhibit TAF1-BD2 bymonitoring the engagement of compound 1000 with a TAF1-BD2 target asdescribed in Example 265.

In certain embodiments the invention provides compound 1001 as describedin Examples 293 and 294, and salts thereof. The invention also providesa method for evaluating a compound's ability to inhibit CECR2 bymonitoring the engagement of compound 1001 with a CECR2 target asdescribed in Example 265

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

Another aspect includes a pharmaceutical composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof.In one embodiment, the composition further comprises a pharmaceuticallyacceptable carrier, adjuvant, or vehicle. In another embodiment, thecomposition further comprises an amount of the compound effective tomeasurably inhibit a bromodomain. In certain embodiments, thecomposition is formulated for administration to a patient in needthereof.

The term “patient” or “individual” as used herein, refers to an animal,such as a mammal, such as a human. In one embodiment, patient orindividual refers to a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions comprising a compound of formula I or salt thereof may beadministered orally, parenterally, by inhalation spray, topically,transdermally, rectally, nasally, buccally, sublingually, vaginally,intraperitoneal, intrapulmonary, intradermal, epidural or via animplanted reservoir. The term “parenteral” as used herein includessubcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques.

In one embodiment, the composition comprising a compound of formula I orsalt thereof is formulated as a solid dosage form for oraladministration. Solid dosage forms for oral administration includecapsules, tablets, pills, powders, and granules. In certain embodiments,the solid oral dosage form comprising a compound of formula (I) or asalt thereof further comprises one or more of (i) an inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate, and (ii) filler or extender such as starches,lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders suchas carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose or acacia, (iv) humectants such as glycerol, (v) disintegratingagent such as agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates or sodium carbonate, (vi) solution retardingagents such as paraffin, (vii) absorption accelerators such asquaternary ammonium salts, (viii) a wetting agent such as cetyl alcoholor glycerol monostearate, (ix) absorbent such as kaolin or bentoniteclay, and (x) lubricant such as talc, calcium stearate, magnesiumstearate, polyethylene glycols or sodium lauryl sulfate. In certainembodiments, the solid oral dosage form is formulated as capsules,tablets or pills. In certain embodiments, the solid oral dosage formfurther comprises buffering agents. In certain embodiments, suchcompositions for solid oral dosage forms may be formulated as fillers insoft and hard-filled gelatin capsules comprising one or more excipientssuch as lactose or milk sugar, polyethylene glycols and the like.

In certain embodiments, tablets, dragees, capsules, pills and granulesof the compositions comprising a compound of formula I or salt thereofoptionally comprise coatings or shells such as enteric coatings. Theymay optionally comprise opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions includepolymeric substances and waxes, which may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polethylene glycols andthe like.

In another embodiment, a composition comprises micro-encapsulatedcompound of formula (I) or salt thereof, and optionally, furthercomprises one or more excipients.

In another embodiment, compositions comprise liquid dosage formulationscomprising a compound of formula I or salt thereof for oraladministration, and optionally further comprise one or more ofpharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In certain embodiments, the liquiddosage form optionally, further comprise one or more of an inert diluentsuch as water or other solvent, a solubilizing agent, and an emulsifiersuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters ofsorbitan, and mixtures thereof. In certain embodiments, liquid oralcompositions optionally further comprise one or more adjuvant, such as awetting agent, a suspending agent, a sweetening agent, a flavoring agentand a perfuming agent.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of formula (I), it is oftendesirable to slow the absorption of the compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

In certain embodiments, the composition for rectal or vaginaladministration are formulated as suppositories which can be prepared bymixing a compound of formula (I) or a salt thereof with suitablenon-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, for example those which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the compound of formula (I).

Example dosage forms for topical or transdermal administration of acompound of formula (I) include ointments, pastes, creams, lotions,gels, powders, solutions, sprays, inhalants or patches. The compound offormula (I) or a salt thereof is admixed under sterile conditions with apharmaceutically acceptable carrier, and optionally preservatives orbuffers. Additional formulation examples include an ophthalmicformulation, ear drops, eye drops, transdermal patches. Transdermaldosage forms can be made by dissolving or dispensing the compound offormula (I) or a salt thereof in medium, for example ethanol ordimethylsulfoxide. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

Nasal aerosol or inhalation formulations of a compound of formula (I) ora salt thereof may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In certain embodiments, pharmaceutical compositions may be administeredwith or without food. In certain embodiments, pharmaceuticallyacceptable compositions are administered without food. In certainembodiments, pharmaceutically acceptable compositions of this inventionare administered with food.

Specific dosage and treatment regimen for any particular patient willdepend upon a variety of factors, including age, body weight, generalhealth, sex, diet, time of administration, rate of excretion, drugcombination, the judgment of the treating physician, and the severity ofthe particular disease being treated. The amount of a provided compoundof formula i or salt thereof in the composition will also depend uponthe particular compound in the composition.

In one embodiment, the therapeutically effective amount of the compoundof the invention administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patientbody weight per day, with the typical initial range of compound usedbeing 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosageforms, such as tablets and capsules, contain from about 5 to about 100mg of the compound of the invention.

An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or saltthereof, and further comprises about 5-30 mg anhydrous lactose, about5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP)K30 and about 1-10 mg magnesium stearate. The process of formulating thetablet comprises mixing the powdered ingredients together and furthermixing with a solution of the PVP. The resulting composition can bedried, granulated, mixed with the magnesium stearate and compressed totablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving about 2-500 mg of a compoundof formula I or salt thereof, in a suitable buffer solution, e.g. aphosphate buffer, and adding a tonicifier, e.g. a salt such sodiumchloride, if desired. The solution may be filtered, e.g. using a 0.2micron filter, to remove impurities and contaminants.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Another aspect includes the use of a compound of formula (I) or a saltthereof for the inhibition of a bromodomain (in vitro or in vivo).

Another embodiment includes a method for treating a bromodomain-mediateddisorder in an animal comprising administering a compound of formula(I), or a pharmaceutically acceptable salt thereof to the animal.Bromodomain-mediated disorders include, but are not limited to thosedisorders described herein.

Another embodiment includes a method of increasing efficacy of a cancertreatment comprising a cytotoxic agent in an animal comprisingadministering to the animal an effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof.

Another embodiment includes a method of delaying or preventingdevelopment of cancer resistance to a cytotoxic agent in an animal,comprising administering to the animal a compound of formula (I) or apharmaceutically acceptable salt thereof.

Another embodiment includes a method of extending the duration ofresponse to a cancer therapy in an animal, comprising administering toan animal undergoing the cancer therapy a compound of formula (I) or apharmaceutically acceptable salt thereof, wherein the duration ofresponse to the cancer therapy when the compound of formula (I) or thepharmaceutically acceptable salt thereof is administered is extendedover the duration of response to the cancer therapy in the absence ofthe administration of the compound of formula (I) or thepharmaceutically acceptable salt thereof.

Another embodiment includes a method of treating cancer in an individualcomprising administering to the individual (a) a compound of formula (I)or a pharmaceutically acceptable salt thereof, and (b) a cytotoxicagent. In one embodiment the cytotoxic agent is selected fromanti-microtubule agents, platinum coordination complexes, alkylatingagents, antibiotic agents, topoisomerase II inhibitors, antimetabolites,topoisomerase I inhibitors, hormones and hormonal analogues, signaltransduction pathway inhibitors, non-receptor tyrosine kinaseangiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents,inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cyclesignaling inhibitors, HDAC inhibitors, proteasome inhibitors, andinhibitors of cancer metabolism. In one embodiment the cytotoxic agentis a taxane. In one embodiment the taxane is paclitaxel or docetaxel. Inone embodiment the cytotoxic agent is a platinum agent. In oneembodiment the cytotoxic agent is an antagonist of EGFR. In oneembodiment the antagonist of EGFR isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine or apharmaceutically acceptable salt thereof (e.g., erlotinib). In oneembodiment the cytotoxic agent is a RAF inhibitor. In one embodiment theRAF inhibitor is a BRAF or CRAF inhibitor. In one embodiment the RAFinhibitor is vemurafenib. In one embodiment the cytotoxic agent is aPI3K inhibitor.

In certain embodiments, treatment may be administered after one or moresymptoms have developed. In other embodiments, treatment may beadministered in the absence of symptoms. For example, treatment may beadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment may also be continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

Bromodomain-Mediated Disorders

A “bromodomain-mediated disorder” is characterized by the participationof one or more bromodomains (e.g., BRD4) in the inception, manifestationof one or more symptoms or disease markers, severity, or progression ofa disorder. Bromodomains include, but are not limited to ASH1L, ATAD2,ATAD2B, BAZ1A, BAZ1B, BAZ2A, BAZ2B, BPTF, BRD1, BRD2, BRD3, BRD4, BRD7,BRD8, BRD9, BRDT, BRPF1, BRPF3, BRWD1, BRWD3, CECR2, CREBBP (aka, CBP),EP300, GCN5L2, KIAA2026, MLL, MLL4, PBRM, PCAF, PHIP, SMARCA2, SMARCA4,SP100, SP110, SP140, SP140L, TAF1, TAF1L, TRIM24, TRIM28, TRIM33,TRIM66, ZMYND8, and ZMYND11.

Bromodomain-mediated disorders include cancers, including, but notlimited to acoustic neuroma, acute leukemia, acute lymphocytic leukemia,acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acuteT-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma,meningioma, mesothelioma, multiple myeloma, myelogenous leukemia,myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC),non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenicsarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas,papillary carcinoma, pinealoma, polycythemia vera, prostate cancer,rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), small cell lungcancer, stomach cancer, squamous cell carcinoma, synovioma, sweat glandcarcinoma, thyroid cancer, Waldenstr6m's macroglobulinemia, testiculartumors, uterine cancer and Wilms' tumor.

In certain embodiments, the cancer is lung cancer, breast cancer,pancreatic cancer, colorectal cancer, and/or melanoma. In certainembodiments, the cancer is lung. In certain embodiments, the lung canceris NSCLC. In certain embodiments, the cancer is breast cancer. Incertain embodiments, the cancer is melanoma.

Bromodomain-mediated disorders also include inflammatory diseases,inflammatory conditions, and autoimmune diseases, including, but notlimited to: Addison's disease, acute gout, ankylosing spondylitis,asthma, atherosclerosis, Beheet's disease, bullous skin diseases,chronic obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis,hypophysitis, inflammatory bowel disease, Kawasaki disease, lupusnephritis, multiple sclerosis, myocarditis, myositis, nephritis, organtransplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis.

Bromodomain-mediated disorders also include AIDS; chronic kidneydiseases, including, but are not limited to diabetic nephropathy,hypertensive nephropathy, HIV-associated nephropathy,glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmentalglomerulosclerosis, membranous glomerulonephritis, minimal changedisease, polycystic kidney disease and tubular interstitial nephritis;acute kidney injury or disease or condition including, but are notlimited to ischemia-reperfusion induced, cardiac and major surgeryinduced, percutaneous coronary intervention induced, radio-contrastagent induced, sepsis induced, pneumonia induced, and drug toxicityinduced; obesity; dyslipidemia; hypercholesterolemia; Alzheimer'sdisease; metabolic syndrome; hepatic steatosis; type II diabetes;insulin resistance; and diabetic retinopathy.

Bromodomain inhibitors may also be used to provide male contraception.

Co-Administration of Compounds and Other Agents

The compounds of formula (I) or salts thereof may be employed alone orin combination with other agents for treatment. For example, the secondagent of the pharmaceutical combination formulation or dosing regimenmay have complementary activities to the compound of formula (I) suchthat they do not adversely affect each other. The compounds may beadministered together in a unitary pharmaceutical composition orseparately. In one embodiment a compound or a pharmaceuticallyacceptable salt can be co-administered with a cytotoxic agent to treatproliferative diseases and cancer.

The term “co-administering” refers to either simultaneousadministration, or any manner of separate sequential administration, ofa compound of formula (I) or a salt thereof, and a further activepharmaceutical ingredient or ingredients, including cytotoxic agents andradiation treatment. If the administration is not simultaneous, thecompounds are administered in a close time proximity to each other.Furthermore, it does not matter if the compounds are administered in thesame dosage form, e.g. one compound may be administered topically andanother compound may be administered orally.

Typically, any agent that has activity against a disease or conditionbeing treated may be co-administered. Examples of such agents can befound in Cancer Principles and Practice of Oncology by V. T. Devita andS. Hellman (editors), 6^(th) edition (Feb. 15, 2001), LippincottWilliams & Wilkins Publishers. A person of ordinary skill in the artwould be able to discern which combinations of agents would be usefulbased on the particular characteristics of the drugs and the diseaseinvolved.

In one embodiment, the treatment method includes the co-administrationof a compound of formula (I) or a pharmaceutically acceptable saltthereof and at least one cytotoxic agent. The term “cytotoxic agent” asused herein refers to a substance that inhibits or prevents a cellularfunction and/or causes cell death or destruction. Cytotoxic agentsinclude, but are not limited to, radioactive isotopes (e.g., At²¹¹,I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², P^(b212) andradioactive isotopes of Lu); chemotherapeutic agents; growth inhibitoryagents; enzymes and fragments thereof such as nucleolytic enzymes; andtoxins such as small molecule toxins or enzymatically active toxins ofbacterial, fungal, plant or animal origin, including fragments and/orvariants thereof.

Exemplary cytotoxic agents can be selected from anti-microtubule agents,platinum coordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Iinhibitors, hormones and hormonal analogues, signal transduction pathwayinhibitors, non-receptor tyrosine kinase angiogenesis inhibitors,immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A;inhibitors of fatty acid biosynthesis; cell cycle signaling inhibitors;HDAC inhibitors, proteasome inhibitors; and inhibitors of cancermetabolism.

“Chemotherapeutic agent” includes chemical compounds useful in thetreatment of cancer. Examples of chemotherapeutic agents includeerlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®,Millennium Pharm.), disulfiram, epigallocatechin gallate,salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactatedehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib(SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis),oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin,Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016,Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, BayerLabs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents suchas thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (includingtopotecan and irinotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);adrenocorticosteroids (including prednisone and prednisolone);cyproterone acetate; 5α-reductases including finasteride anddutasteride); vorinostat, romidepsin, panobinostat, valproic acid,mocetinostat dolastatin; aldesleukin, talc duocarmycin (including thesynthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; asarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,chlomaphazine, chlorophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, and ranimnustine; antibiotics such as the enediyneantibiotics (e.g., calicheamicin, especially calicheamicin γ1I andcalicheamicin ω1I (Angew Chem. Intl. Ed Engl. 1994 33:183-186);dynemicin, including dynemicin A; bisphosphonates, such as clodronate;an esperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid, eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR®(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinumanalogs such as cisplatin and carboplatin; vinblastine; etoposide(VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE®(vinorelbine); novantrone; teniposide; edatrexate; daunomycin;aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such asretinoic acid; and pharmaceutically acceptable salts, acids andderivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that actto regulate or inhibit hormone action on tumors such as anti-estrogensand selective estrogen receptor modulators (SERMs), including, forexample, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene,droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene,LY117018, onapristone, and FARESTON® (toremifine citrate); (ii)aromatase inhibitors that inhibit the enzyme aromatase, which regulatesestrogen production in the adrenal glands, such as, for example,4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate),AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR®(vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole;AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide and goserelin; buserelin, tripterelin,medroxyprogesterone acetate, diethylstilbestrol, premarin,fluoxymesterone, all transretionic acid, fenretinide, as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN®, rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceuticallyacceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab(Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®,Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®,Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech),trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), andthe antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).Additional humanized monoclonal antibodies with therapeutic potential asagents in combination with the compounds of the invention include:apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine,cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab,cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab,felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin,ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab,motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab,numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab,pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab,ustekinumab, visilizumab, and the anti-interleukin-12 (ABT-874/J695,Wyeth Research and Abbott Laboratories) which is a recombinantexclusively human-sequence, full-length IgG₁λ antibody geneticallymodified to recognize interleukin-12 p40 protein.

Chemotherapeutic agent also includes “EGFR inhibitors,” which refers tocompounds that bind to or otherwise interact directly with EGFR andprevent or reduce its signaling activity, and is alternatively referredto as an “EGFR antagonist.” Examples of such agents include antibodiesand small molecules that bind to EGFR. Examples of antibodies which bindto EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507),MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No.4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized225 (C225 or Cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see, WO96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targetedantibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat.No. 5,212,290); humanized and chimeric antibodies that bind EGFR asdescribed in U.S. Pat. No. 5,891,996; and human antibodies that bindEGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen);EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996));EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR thatcompetes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); humanEGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known asE1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described inU.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanizedmAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). Theanti-EGFR antibody may be conjugated with a cytotoxic agent, thusgenerating an immunoconjugate (see, e.g., EP659,439A2, Merck PatentGmbH). EGFR antagonists include small molecules such as compoundsdescribed in U.S. Pat. Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307,5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726,6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459,6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, aswell as the following PCT publications: WO98/14451, WO98/50038,WO99/09016, and WO99/24037. Particular small molecule EGFR antagonistsinclude OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSIPharmaceuticals); PD 183805 (CI 1033, 2-propenamide,N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-,dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®)4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline,AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline,Zeneca); BIBX-1382(N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methylpiperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine,Boehringer Ingelheim); PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine);CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide);EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide)(Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 orN-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6 [5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include “tyrosine kinase inhibitors”including the EGFR-targeted drugs noted in the preceding paragraph;small molecule HER2 tyrosine kinase inhibitor such as TAK165 availablefrom Takeda; CP-724,714, an oral selective inhibitor of the ErbB2receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such asEKB-569 (available from Wyeth) which preferentially binds EGFR butinhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016;available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinaseinhibitor, PKI-166 (available from Novartis); pan-HER inhibitors such ascanertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisenseagent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1signaling; non-HER targeted TK inhibitors such as imatinib mesylate(GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosinekinase inhibitors such as sunitinib (SUTENT®, available from Pfizer);VEGF receptor tyrosine kinase inhibitors such as vatalanib(PTK787/ZK222584, available from Novartis/Schering AG); MAPKextracellular regulated kinase I inhibitor CI-1040 (available fromPharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines,such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines,4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloylmethane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containingnitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules(e.g. those that bind to HER-encoding nucleic acid); quinoxalines (U.S.Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474(Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors suchas CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinibmesylate (GLEEVECO); PKI 166 (Novartis); GW2016 (Glaxo SmithKline);CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474(AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone),rapamycin (sirolimus, RAPAMUNE®); or as described in any of thefollowing patent publications: U.S. Pat. No. 5,804,396; WO 1999/09016(American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983(Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (WarnerLambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons,colchicine, metoprine, cyclosporine, amphotericin, metronidazole,alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide,asparaginase, BCG live, bevacuzimab, bexarotene, cladribine,clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa,elotinib, filgrastim, histrelin acetate, ibritumomab, interferonalfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna,methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin,palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim,pemetrexed disodium, plicamycin, porfimer sodium, quinacrine,rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene,tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, andpharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisoneacetate, cortisone acetate, tixocortol pivalate, triamcinoloneacetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide,desonide, fluocinonide, fluocinolone acetonide, betamethasone,betamethasone sodium phosphate, dexamethasone, dexamethasone sodiumphosphate, fluocortolone, hydrocortisone-17-butyrate,hydrocortisone-17-valerate, aclometasone dipropionate, betamethasonevalerate, betamethasone dipropionate, prednicarbate,clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolonecaproate, fluocortolone pivalate and fluprednidene acetate; immuneselective anti-inflammatory peptides (ImSAIDs) such asphenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG)(IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such asazathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts,hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumornecrosis factor alpha (TNFα) blockers such as etanercept (Enbrel),infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia),golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra(Kineret), T cell costimulation blockers such as abatacept (Orencia),Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®);Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha(IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such asrhuMAb Beta7; IgE pathway blockers such as Anti-Mi prime; Secretedhomotrimeric LTa3 and membrane bound heterotrimer LTa1/β2 blockers suchas Anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹,I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactiveisotopes of Lu); miscellaneous investigational agents such asthioplatin, PS-341, phenylbutyrate, ET-18-OCH₃, or farnesyl transferaseinhibitors (L-739749, L-744832); polyphenols such as quercetin,resveratrol, piceatannol, epigallocatechine gallate, theaflavins,flavanols, procyanidins, betulinic acid and derivatives thereof;autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol(dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinicacid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin);podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®);bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®),etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®),alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), orrisedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R);vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g.celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779;tipifamib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersensodium (GENASENSE®); pixantrone; famesyltransferase inhibitors such aslonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts,acids or derivatives of any of the above; as well as combinations of twoor more of the above such as CHOP, an abbreviation for a combinedtherapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone;and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin(ELOXATIN™) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatorydrugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDsinclude non-selective inhibitors of the enzyme cyclooxygenase. Specificexamples of NSAIDs include aspirin, propionic acid derivatives such asibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen,acetic acid derivatives such as indomethacin, sulindac, etodolac,diclofenac, enolic acid derivatives such as piroxicam, meloxicam,tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivativessuch as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamicacid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib,parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicatedfor the symptomatic relief of conditions such as rheumatoid arthritis,osteoarthritis, inflammatory arthropathies, ankylosing spondylitis,psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea,metastatic bone pain, headache and migraine, postoperative pain,mild-to-moderate pain due to inflammation and tissue injury, pyrexia,ileus, and renal colic.

Chemotherapeutic agents also include treatments for Alzheimer's Diseasesuch as donepezil hydrochloride and rivastigmine; treatments forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole,pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine;agents for treating multiple sclerosis (MS) such as beta interferon(e.g., Avonexo® and Rebif®), glatiramer acetate, and mitoxantrone;treatments for asthma such as albuterol and montelukast sodium; agentsfor treating schizophrenia such as zyprexa, risperdal, seroquel, andhaloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

Additionally, chemotherapeutic agents include pharmaceuticallyacceptable salts, acids or derivatives of any of chemotherapeuticagents, described herein, as well as combinations of two or more ofthem.

For treating an inflammatory disease or an autoimmune disease, acompound of formula (I) or a pharmaceutically acceptable salt thereofmay be co-administered with methotrexate, tofacitinib, 6-mercaptopurine,azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquinine, penicillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled, and local injection), a beta-2 adrenoreceptor agonist(salbutamol, terbutaline, salmeteral), a xanthine (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, an NSAID (e.g. ibuprofen), a corticosteroid (e. g.prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, anantithrombotic agent, a complement inhibitor, an adrenergic agent, anagent that interferes with signalling by proinflammatory cytokines suchas TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1converting enzyme inhibitor, a T-cell signalling inhibitor (e.g. akinase inhibitor), a metalloproteinase inhibitor, sulfasalazine, a6-mercaptopurine, an angiotensin converting enzyme inhibitor, a solublecytokine receptor (e.g. soluble p55 or p75 TNF receptors and thederivatives p75TNFRigG (etanercept) and p55TNFRigG (Lenercept), siL-1RI,siL-1RII, siL-6R), an antiinflammatory cytokine (e.g. IL-4, IL-10,IL-11, IL-13 and TGF), celecoxib, folic acid, hydroxychloroquinesulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab,tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine,methylprednisolone, meloxicam, methylprednisolone acetate, gold sodiumthiomalate, aspirin, triamcinolone acetonide, propoxyphenenapsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac,diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodonebitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,acetaminophen, alendronate sodium, prednisolone, cortisone,betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin,glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine, oxycodoneHCVacetaminophen, olopatadine HCl misoprostol, naproxen sodium,omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, Anti-ILLS, BIRB-796, SCI0-469, VX-702, AMG-548, VX-740,Roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), a PKCfamily inhibitor (e.g. Ruboxistaurin or AEB-071) or Mesopram. In certainembodiments, a compound of formula (I) or a pharmaceutically acceptablesalt thereof may be co-administered with methotrexate or leflunomide. Inmoderate or severe rheumatoid arthritis cases, a compound of formula (I)or a pharmaceutically acceptable salt thereof may be co-administeredwith cyclosporine and anti-TNF antibodies as noted above. A compound offormula (I) or a pharmaceutically acceptable salt thereof may also beco-administered with: budenoside; epidermal growth factor; acorticosteroid; cyclosporin, sulfasalazine; an aminosalicylate;6-mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor;mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxaneinhibitor; an IL-1 receptor antagonist; an anti-IL-1 monoclonalantibody; an anti-IL-6 monoclonal antibody; a growth factor; an elastaseinhibitor; a pyridinyl-imidazole compound; an antibody to or antagonistof other human cytokines or growth factors (e.g. TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF); a cell surface molecule (e.g. CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, or CD90 or their ligands); methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; anNSAID (e.g. ibuprofen); a corticosteroid (e.g. prednisolone); aphosphodiesterase inhibitor; an adenosine agonist; an antithromboticagent; a complement inhibitor, an adrenergic agent; an agent thatinterferes with signalling by proinflammatory cytokines such as TNF 5 orIL-1 (e.g. a NIK, IKK, or MAP kinase inhibitor); an IL-1 convertingenzyme inhibitor; a TNF converting enzyme inhibitor; a T-cell signallinginhibitor such as kinase inhibitors; a metalloproteinase inhibitor;sulfasalazine; azathioprine; a 6-mercaptopurine; an angiotensinconverting enzyme inhibitor; a soluble cytokine receptor (e.g. solublep55 or p75 TNF receptors, siL-1RI, siL-1RII, siL-6R), and anantiinflammatory cytokine (e.g. IL-4, IL-10, IL-11, IL-13 or TGF).

For treating Crohn's disease, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered with aTNF antagonist (e.g. an anti-TNF antibody), D2E7 (adalimumab), CA2(infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG (etanercept)), ap55TNFRigG (LENERCEPT™) inhibitor, or a PDE4 inhibitor.

For treating inflammatory bowel disease, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered with acorticosteroid (e.g. budenoside or dexamethasone); sulfasalazine,5-aminosalicylic acid; olsalazine; an agent that interferes withsynthesis or action of proinflammatory cytokines such as IL-1 (e.g. anIL-1 converting enzyme inhibitor or IL-Ira); a T cell signalinginhibitor (e.g. a tyrosine kinase inhibitor); 6-mercaptopurine; IL-11;mesalamine; prednisone; azathioprine; mercaptopurine; infliximab;methylprednisolone sodium succinate; diphenoxylate/atrop sulfate;loperamide hydrochloride; methotrexate; omeprazole; folate;ciprofloxacin/dextrose-water; hydrocodone bitartrate/apap; tetracyclinehydrochloride; fluocinonide; metronidazole; thimerosal/boric acid;cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyaminesulfate; meperidine hydrochloride; midazolam hydrochloride; oxycodoneHCl/acetaminophen; promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab or interferon-gamma.

For treating multiple sclerosis, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered with acorticosteroid; prednisolone; methylprednisolone; azathioprine;cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine;tizanidine; interferon-la (AVONEX®; Biogen); interferon-lb (BETASERON®;Chiron/Berlex); interferon-n3) (Interferon Sciences/Fujimoto),interferon-(Alfa Wassermnnann/J&J), interferon IA-IF (Serono/InhaleTherapeutics), Peginterferon 2b (Enzon/Schering-Plough), Copolymer 1(Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaricoxygen; intravenous immunoglobulin; cladribine; an antibody to orantagonist of other human cytokines or growth factors and theirreceptors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23,1L-15, IL-16, EMAP-II, GM-CSF, FGF, or PDGF).

For treating AIDS a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with antibodies to cellsurface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28,CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound ofFormula (I) or a pharmaceutically acceptable salt thereof may also beco-administered with methotrexate, cyclosporine, FK506, rapamycin,mycophenolate mofetil, leflunomide, an S1P1 agonist, an NSAID (e.g.ibuprofen), a corticosteroid (e.g. prednisolone), a phosphodiesteraseinhibitor, an adensosine agonist, an antithrombotic agent, a complementinhibitor, an adrenergic agent, an agent that interferes with signallingby proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor, a TACEinhibitor, a T-cell signaling inhibitor (e.g. a kinase inhibitor), ametalloproteinase inhibitor, sulfasalazine, azathioprine, a6-mercaptopurine, an angiotensin converting enzyme inhibitor, a solublecytokine receptor (e.g. soluble p55 or p75 TNF receptors, siL-1RI,siL-1RII, or siL-6R), or an antiinflammatory cytokine (e.g. IL-4, IL-10,IL-13 or TGF).

A compound of formula (I) or a pharmaceutically acceptable salt thereofmay also be co-administered with agents, such as alemtuzumab,dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride,fampridine, glatiramer acetate, natalizumab, sinnabidol, immunokineNNSO3, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778,calagualine, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD(cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, ananti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258(RDP-1258), sTNF-RI, talampanel, teriflunomide, TGF-beta2, tiplimotide,a VLA-4 antagonist (e.g. TR-14035, VLA4 Ultrahaler, orAntegran-ELAN/Biogen), an interferon gamma antagonist, or an IL-4agonist.

For treating ankylosing spondylitis a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered withibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin,diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate,azathioprine, minocyclin, prednisone, an anti-TNF antibody, D2E7(HUMIRA®), CA2 (infliximab), CDP 571, a TNFR-Ig construct, (p75TNFRigG(ENBREL®), or p55TNFRigG (LENERCEPT®).

For treating asthma a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with albuterol,salmeterol/fluticasone, montelukast sodium, fluticasone propionate,budesonide, prednisone, salmeterol xinafoate, levalbuterol HCl,albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, cromolyn sodium, fexofenadine hydrochloride,flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, guaifenesin,dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline hyclate,guaifenesin/d-methorphan, p-ephedrine/cod/-chlorphenir, gatifloxacin,cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate,benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizineHCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine,cefprozil, dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, an anti-IL-13 antibody, ormetaproterenol sulfate.

For treating COPD a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with albuterolsulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone,albuterol, salmeterol xinafoate, fluticasone propionate, prednisone,theophylline anhydrous, methylprednisolone sodium succinate, montelukastsodium, budesonide, formoterol fumarate, triamcinolone acetonide,levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate,levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillintrihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate,flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenolsulfate, methylprednisolone, mometasone furoate,p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine,terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT,cilomilast, or roflumilast.

For treating psoriasis, a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with calcipotriene,clobetasol propionate, triamcinolone acetonide, halobetasol propionate,tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented,fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate,mometasone furoate, ketoconazole, pramoxine/fluocinolone, hydrocortisonevalerate, flurandrenolide, urea, betamethasone, clobetasolpropionate/emoll, fluticasone propionate, azithromycin, hydrocortisone,moisturizing formula, folic acid, desonide, pimecrolimus, coal tar,diflorasone diacetate, etanercept folate, lactic acid, methoxsalen,he/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone,sunscreen, halcinonide, salicylic acid, anthralin, clocortolonepivalate, coal extract, coal tar/salicylic acid, coal tar/salicylicacid/sulfur, desoximetasone, diazepam, emollient,fluocinonide/emollient, mineral oil/castor oil/na lact, mineraloil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid,soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab,cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA,UVB, sulfasalazine, ABT-874 or ustekinamab.

For treating psoriatic arthritis, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered withmethotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), orefalizumab.

For treating lupus, a compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be co-administered with an NSAID (e.g.diclofenac, naproxen, ibuprofen, piroxicam, or indomethacin); a COX2inhibitor (e.g. celecoxib, rofecoxib, or valdecoxib); an anti-malarial(e.g. hydroxychloroquine); a steroid (e.g. prednisone, prednisolone,budenoside, or dexamethasone); a cytotoxic (e.g. azathioprine,cyclophosphamide, mycophenolate mofetil, or methotrexate); an inhibitorof PDE4, or a purine synthesis inhibitor (e.g. Cellcept®). For example,a compound of formula (I) or a pharmaceutically acceptable salt thereofmay be co-administered with sulfasalazine, 5-aminosalicylic acid,olsalazine, Imuran®, an agent that interferes with the synthesis,production, or action of a proinflammatory cytokine (e.g. IL-1), or acaspase inhibitor (e.g. a IL-1 converting enzyme inhibitor or IL-Ira).

A compound of formula (I) or a pharmaceutically acceptable salt thereofmay also be co-administered with a T cell signaling inhibitor (e.g. atyrosine kinase inhibitor), or a molecule that targets T cell activation(e.g. CTLA-4-IgG, an anti-B7 family antibody, or an anti-PD-1 familyantibody).

A compound of formula (I) or a pharmaceutically acceptable salt thereofcan also be co-administered with an IL-11 antibody, an anti-cytokineantibody (e.g. fonotolizumab (anti-IFNg antibody)), or an anti-receptorreceptor antibodies (e.g. an anti-IL-6 receptor antibody or an antibodyto a B-cell surface molecule).

A compound of formula (I) or a pharmaceutically acceptable salt thereofcan also be co-administered with LJP 394 (abetimus), an agent thatdepletes or inactivates B-cells (e.g. Rituximab (anti-CD20 antibody) orlymphostat-B (anti-BlyS antibody)), a TNF antagonist (e.g. an anti-TNFantibody), D2E7 (adalimumab), CA2 (infliximab), CDP 571, a TNFR-Igconstruct, (p75TNFRigG (etanercept), or p55TNFRigG (LENERCEPT™).

A compound of formula (I) or a pharmaceutically acceptable salt thereofcan also be co-administered with one or more agents used in theprevention or treatment of AIDS: an HIV reverse transcriptase inhibitor,an HIV protease inhibitor, an immunomodulator, or another retroviraldrug. Examples of reverse transcriptase inhibitors include, but are notlimited to, abacavir, adefovir, didanosine, dipivoxil delavirdine,efavirenz, emtricitabine, lamivudine, nevirapine, rilpivirine,stavudine, tenofovir, zalcitabine, and zidovudine. Examples of proteaseinhibitors include, but are not limited to, amprenavir, atazanavir,darunavir, indinavir, fosamprenavir, lopinavir, nelfinavir, ritonavir,saquinavir, and tipranavir. Examples of other retroviral drugs include,but are not limited to, elvitegravir, enfuvirtide, maraviroc andraltegravir.

For treating type II diabetes, hepatic steatosis, insulin resistance,metabolic syndrome or a related disorder, a compound of formula (I) or apharmaceutically acceptable salt thereof may be co-administered withinsulin or insulins that have been modified to improve the duration ofaction in the body; agents that stimulate insulin secretion such asacetohexamide, chlorpropamide, glyburide, glimepiride, glipizide,glicazide, glycopyramide, gliquidone, rapaglinide, nataglinide,tolazamide or tolbutamide; agents that are glucagon-like peptideagonists such as exanatide, liraglutide or taspoglutide; agents thatinhibit dipeptidyl-peptidase IV such as vildagliptin, sitagliptin,saxagliptin, linagliptin, allogliptin or septagliptin; agents that bindto the peroxisome proliferator-activated receptor gamma such asrosiglitazone or pioglitazone; agents that decrease insulin resistancesuch as metformin; or agents that reduce glucose absorbance in the smallintestine such as acarbose, miglitol or voglibose.

For treating acute kidney disorders or a chronic kidney disease, acompound of formula (I) or a pharmaceutically acceptable salt thereofmay be co-administered with dopamine, a diuretic (e.g. furosemide),bumetanide, thiazide, mannitol, calcium gluconate, sodium bicarbonate,albuterol, paricalcitol, doxercalciferol, cinacalcet, or bardoxalonemethyl.

The amount of both the compound of formula (I) or salt thereof andadditional agent (in those compositions which comprise an additionaltherapeutic agent as described above) that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Incertain embodiments, compositions of this invention are formulated suchthat a dosage of between 0.01-100 mg/kg body weight/day of an inventivecan be administered.

The additional therapeutic agent and the compound of formula (I) may actsynergistically. Therefore, the amount of additional therapeutic agentin such compositions may be less than that required in a monotherapyutilizing only that therapeutic agent, or there may be fewer sideeffects for the patient given that a lower dose is used. In certainembodiments, in such compositions a dosage of between 0.01-1,000 μg/kgbody weight/day of the additional therapeutic agent can be administered.

Provided herein are methods of extending the duration of response to acytotoxic agent in an individual with cancer comprising administering tothe individual (a) an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof and (b) an effective amount ofthe cytotoxic agent.

In certain embodiments of any of the methods, the cytotoxic agent is atargeted therapy. In certain embodiments, the targeted therapy is one ormore of an EGFR antagonist, RAF inhibitor, and/or PI3K inhibitor.

In certain embodiments of any of the methods, the targeted therapy is anEGFR antagonist. In certain embodiments of any of the methods, the EGFRantagonist isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine and/or apharmaceutical acceptable salt thereof. In certain embodiments, the EGFRantagonist isN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Incertain embodiments, the EGFR antagonist isN-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine,di4-methylbenzenesulfonateor a pharmaceutically acceptable salt thereof (e.g., lapatinib).

In certain embodiments of any of the methods, targeted therapy is a RAFinhibitor. In certain embodiments, the RAF inhibitor is a BRAFinhibitor. In certain embodiments, the RAF inhibitor is a CRAFinhibitor. In certain embodiments, the BRAF inhibitor is vemurafenib. Incertain embodiments, the RAF inhibitor is3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamideor a pharmaceutically acceptable salt thereof (e.g., AZ628(CAS#878739-06-1)).

In certain embodiments of any of the methods, the targeted therapy is aPI3K inhibitor.

In certain embodiments of any of the methods, the cytotoxic agent ischemotherapy. In certain embodiments of any of the methods, thechemotherapy is a taxane. In certain embodiments, the taxane ispaclitaxel. In certain embodiments, the taxane is docetaxel.

In certain embodiments of any of the methods, the cytotoxic agent is aplatinum agent. In certain embodiments, the platinum agent iscarboplatin. In certain embodiments, the platinum agent is cisplatin. Incertain embodiments of any of the methods, the cytotoxic agent is ataxane and a platinum agent. In certain embodiments, the taxane ispaclitaxel. In certain embodiments, the taxane is docetaxel. In certainembodiments, the platinum agent is carboplatin. In certain embodiments,the platinum agent is cisplatin.

In certain embodiments of any of the methods, the cytotoxic agent is avinca alkyloid. In certain embodiments, the vinca alkyloid isvinorelbine. In certain embodiments of any of the methods, thechemotherapy is a nucleoside analog. In certain embodiments, thenucleoside analog is gemcitabine.

In certain embodiments of any of the methods, the cytotoxic agent isradiotherapy.

In certain embodiments of any of the methods, the compound of formula(I) or a pharmaceutically acceptable salt thereof is concomitantlyadministered with the cytotoxic agent (e.g., targeted therapy,chemotherapy, and/or radiotherapy). In certain embodiments, the compoundof formula (I) or a pharmaceutically acceptable salt thereof isadministered prior to and/or concurrently with the cytotoxic agent(e.g., targeted therapy, chemotherapy, and/or radiotherapy).

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Representative Compounds of formula (I) were prepared according to thescheme shown above. Intermediate A (prepared as described below) wasconverted into the corresponding methyl ester under Pd-catalyzedcarbonylation conditions, and the resultant intermediates were alkylatedwith various R¹-halides. Hydrolysis of those esters simultaneouslyremoved the tosyl protecting group and revealed the carboxylic acid,which was coupled with various amines to yield compounds of formula (I).

Representative compounds of formula (I) were prepared according to thescheme shown above. Intermediate A (prepared as described below) wasalkylated with various R¹-halides before being converted into thecorresponding carboxylic acids under Pd-catalyzed carbonylationconditions. Subsequent amide bond formation, followed by hydrolyticremoval of the tosyl group, yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to thescheme shown above. Variously N-substituted derivatives of tert-butyl4-(2-(7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamido)ethyl)piperidine-1-carboxylate(prepared as in Generic Scheme A) were protected with tosyl chlorideunder basic conditions. The resultant compounds were alkylated withR^(c)-halides on the amide nitrogen before acidic removal of the Bocprotecting group. Reductive amination with various aldehydes introducedsubstituents on the piperidine, and subsequent hydrolytic removal of thetosyl group yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to thescheme shown above. Variously pyrrolopyridone N-substituted derivativesof tert-butyl4-((N-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamido)methyl)piperidine-1-carboxylate(prepared as in Generic Scheme A) were deprotected under acidicconditions. Reductive amination of the resultant amines with variousaldehydes yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to thescheme shown above. Variously pyrrolopyridone N-substituted derivativesof tert-butyl4-(N-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamido)piperidine-1-carboxylate(prepared as in Generic Scheme A) were deprotected under acidicconditions. Reductive amination of the resultant amines with variousaldehydes yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to thescheme shown above. Variously pyrrolopyridone N-substituted derivativesof tert-butyl4-methyl-4-((7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamido)methyl)piperidine-1-carboxylate(prepared as in Generic Scheme A) were deprotected under acidicconditions. Reductive amination of the resultant amines with variousaldehydes yielded compounds of formula (I).

Representative compounds of formula (I) were prepared according to thescheme shown above. Variously pyrrolopyridone N-substituted derivativesofN-methyl-7-oxo-N-(piperidin-4-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride (prepared as in Generic Scheme A) were alkylated on thepiperidine nitrogen to yield compounds of formula (I).

Representative compounds of formula (I) were prepared according to thescheme shown above. Intermediate D (prepared as described below) wasconverted into compounds of formula (I) by Pd-catalyzed aminocarbonylation in the presence of variously substituted amines.

Step 1: 2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol) inmethanol (1.0 L) was added dropwise (2 h) to a stirred and cooled (0°C.) solution of sodium methoxide (250 g, 4.63 mol) in methanol (850 mL).After addition, the mixture was heated to reflux for 23 h, at which timeTLC indicated the reaction had gone to completion. The mixture wasconcentrated under reduced pressure to a volume of approximately 900 mL,and quenched by addition of water (1.5 L). The resulting solid wascollected by filtration, washed with water and dried under reducedpressure to give the title compound (250 g, 100% yield) as a brownsolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J=5.2 Hz, 1H), 7.10 (d,J=5.6 Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H).

Step 2: 5-bromo-2-methoxy-4-methyl-3-nitropyridine

Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid (1.5L) at ambient temperature and then Br₂ (639 g, 4.00 mol) was addeddropwise (30 min). After addition, the mixture was heated at 80° C. for12 h, at which time TLC indicated the reaction had gone to completion.The mixture was cooled (0° C.) and quenched by sequential addition of10% aqueous (1.5 L) and saturated aqueous Na₂SO₃ (1.5 L). The resultingsolid was collected by filtration washed with water, and dried underreduced pressure to give the title compound (302 g, 82.2% yield) as alight yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 3.94 (s,3H), 2.29 (s, 3H).

Step 3:(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine

DMF-DMA (600 mL) was slowly added to a stirred and heated (80° C.)solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol)in DMF (1.1 L). After addition, the mixture was heated at 95° C. for 5h, at which time TLC indicated the reaction had gone to completion. Themixture was cooled to room temperature and poured into ice-cold water (3L). The resulting red solid was collected by filtration, washed withwater, and dried under reduced pressure to give the title compound (167g, 100% yield) as red solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H),7.05 (d, J=13.6 Hz, 1H), 7.05 (d, J=13.6 Hz, 1H), 4.80 (d, J=13.2 Hz,1H), 3.88 (s, 3H), 2.90 (s, 6H).

Step 4: 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

A mixture of2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (50.0g, 165 mmol), Fe (50.0 g, 893 mmol) and NH₄Cl (50.0 g, 943 mmol) inmethanol/H₂O (1900/250 mL) was heated at reflux for 7 h, at which timeLCMS indicated that the reaction had gone to completion. The mixture wasfiltered while hot and the cake was washed with methanol (3×200 mL). Thecombined filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel chromatography (petroleumether: Ethyl acetate=5:1) to give the crude product. This crude materialwas triturated with acetonitrile to give the title compound (37.4 g,99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7, 228.7.

Step 5: 4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine

A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g, 0.15mol) in THF (700 mL) was added dropwise to a stirred and cooled (0° C.)solution of sodium hydride (60%, 19.2 g, 0.48 mol) in THF (700 mL).After addition, the mixture was stirred at room temperature for 1 h, andthen cooled again to 0° C. Tosyl chloride (38.0 g, 0.20 mol) in THF (700mL) was added dropwise and the resulting mixture was stirred at ambienttemperature for 2 h. The reaction was quenched by addition of saturatedaqueous ammonium chloride (1.0 L), and then extracted with ethyl acetate(3×600 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was triturated withacetonitrile to give the title compound (51.2 g, 88.9% yield) as a brownsolid. This crude material was used in the next step without furtherpurification.

Step 6: 4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one

HBr (40% aqueous, 1.1 L) was added to a solution of4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (102.5 g,0.27 mol) in ethanol (200 mL). After addition, the mixture was heated at90° C. for 2 h, at which time TLC indicated that the reaction had goneto completion. The mixture was cooled to 0° C. and the resulting whitesolid was collected by filtration. This solid was washed with water anddried under vacuum to give the title compound (Intermediate A) (87.5 g,88.6% yield) as a light brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.48(s, 1H), 8.01 (d, J=3.6 Hz, 1H), 8.90 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0Hz, 2H), 7.32 (s, 1H), 6.57 (d, J=3.2 Hz, 1H), 2.34 (s, 3H).

Step 7: methyl7-oxo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridine-4-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride (5.0 g,8.5 mmol) was added to a mixture of4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one (10.0 g, 27.3mmol), Et₃N (20.0 mL, 143.5 mmol) in methanol (1 L). After addition, themixture was stirred under CO atmosphere (50 psi) at 80° C. for 24 h, atwhich time TLC (petroleum ether:ethyl acetate=1:1) showed the completionof the reaction. The resulting mixture was concentrated under reducedpressure and the residue was purified by flash column (petroleum ether:ethyl acetate=5:1 to 3:1) to give the title compound (Intermediate B)(7.5 g, 79.5% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ11.79 (s, 1H), 8.03 (d, J=3.6 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.80 (s,1H), 7.37 (d, J=8.0 Hz, 2H), 7.05 (d, J=3.2 Hz, 1H), 3.77 (s, 3H), 2.33(s, 3H).

Step 8: methyl6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylate

Methyl iodide (18.1 g, 127.24 mmol) was added dropwise to a stirredsolution of methyl7-oxo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridine-4-carboxylate (11.6g, 33.49 mmol) and Cs₂CO₃ (13.1 g, 40.18 mmol) in dioxane (230 mL).After addition, the resulting mixture was stirred at room temperaturefor 4 hr, at which time TLC indicated the reaction was completed. Thesolid was removed by filtration and the filtrate was concentrated. Theresidue was dissolved in ethyl acetate (250 mL) and washed with water(50 mL×2). The organic layer was dried over sodium sulfate andconcentrated under reduced pressure to give the title compound (11.0 g,91.1% yield) as a white solid. This crude was used into next stepwithout further purification. LCMS M/Z (M+H) 360.9.

Step 9: 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid

Sodium hydroxide (6.0 g, 150.0 mmol) was added in portions to a stirredsolution of methyl6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylate(12.0 g, 33.3 mmol) in methanol/water (260/30 mL). After addition, themixture was stirred at 80° C. for 2 h, at which time LCMS indicated thereaction had gone to completion. After cooling, the mixture wasconcentrated under reduced pressure. The residue was dissolved in water(30 mL) and the aqueous solution was acidified to pH 3-4 using 5 Nhydrochloric acid. The resulting precipitate was collected byfiltration, washed with water, and dried under reduced pressure to givethe title compound (Intermediate C) (4.3 g, 67.2% yield) as a brownsolid. This crude material was used in the next step without furthertreatment. LCMS M/Z (M+H) 192.8.

General Procedure for the Preparation of Intermediates D, E

4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-e]pyridin-7-one

Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirredsuspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(Intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g, 54.6mmol) in dioxane (250 mL). After addition, the reaction mixture wasstirred at room temperature for 18 h, at which time LCMS indicated thereaction had gone to completion. The solvent was evaporated underreduced pressure, and the residue was diluted with water (200 mL). Themixture was extracted with EtOAc (3×200 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=3:1) to give the title compound(Intermediate D) (14.0 g, 81.4% yield) as a brown solid. ¹H NMR (400MHz, DMSO-d6): δ 8.03 (d, J=3.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.78(s, 1H), 7.39 (d, J=8.4 Hz, 2H), 6.57 (d, J=3.6 Hz, 1H), 3.35 (s, 3H),2.35 (s, 3H).

6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylicacid

A disposable tube was charged with4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one(Intermediate D), 2 g, 5.25 mmol), 1,3-bis(dicyclohexylphosphino)propane(0.642 g, 1.049 mmol), palladium acetate (0.118 g, 0.525 mmol), andpotassium carbonate (1.450 g, 10.49 mmol) before being evacuated andpurged with carbon monoxide three times. Water (0.189 ml, 10.49 mmol)and dimethylsulfoxide (5 mL) were added, and the mixture was stirred at100° C. for 6 h. The reaction mixture was cooled and diluted with ethylacetate (100 mL). The crude product was extracted with 1 N aqueoussodium hydroxide. This aqueous extract was then acidified using 1 Nhydrochloric acid resulting in formation of a precipitate. This materialwas collected and lyophilized to yield title compound (Intermediate E)(1.08 g, 59%) as a grey amorphous solid that was used crude insubsequent reactions. LCMS M/Z (M+H) 347.

General Procedure for Intermediate F

Step 1: 5-bromo-2-methoxy-3-nitropyridine

Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) in methanol (125mL). After addition, the reaction mixture was heated at reflux for 2 h.The mixture was concentrated under reduced pressure, and the residue wasdiluted with water (200 mL). The resulting precipitate was collected byfiltration, washed with water, and dried under reduced pressure to givethe title compound (12.0 g, 81.5% yield) as a brown solid. ¹H NMR (400MHz, CDCl₃): δ 8.43 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 4.09 (s,3H).

Step 2: 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine

Isopropenyl magnesium bromide (0.5 M in THF, 105.0 mL, 55.0 mmol) wasadded dropwise to a stirred and cooled (−78° C.) solution of5-bromo-2-methoxy-3-nitropyridine (4.0 g, 17.1 mmol) in THF (40 mL).After addition, the resulting mixture was allowed to warm to roomtemperature gradually and stirred for an additional 3 h. The reactionmixture was quenched by addition of 1 M aqueous ammonium chloride (150mL), and then extracted with ethyl acetate (3×100 mL). The combinedorganic extracts were dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatography(petroleum ether: ethyl acetate=10:1) to give the title compound (1.65g, 39.9% yield) as brown oil. LCMS M/Z (M+H) 240/242.

Step 3: 4-bromo-2-methyl-1,6-dihydropyrrolo[2,3-c]pyridin-7-one

Hydrogen bromide (40% aqueous, 20 mL) was added to a solution of4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine (1.65 g, 6.8 mmol)in ethanol (10 mL). After addition, the reaction mixture was heated at90° C. for 15 h, at which time TLC indicated the reaction had gone tocompletion. The mixture was cooled to 0° C. and the resulting solid wascollected by filtration. This solid was washed with water and dried togive title compound (0.9 g, 57.9% yield) as a brown solid. ¹H NMR (400MHz, DMSO-d6): δ 12.06 (s, 1H), 11.00 (s, 1H), 7.03 (s, 1H), 5.97 (s,1H), 2.29 (s, 3H). LCMS M/Z (M+H) 226/228

Step 4:6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylicacid (Intermediate F)

To a solution of methyl2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylate (10.0g, 48.5 mmol) in DMF (100 mL) was added K₂CO₃ (20.1 g, 145.0 mmol) andallyl bromide (5.9 g, 48.5 mmol). After addition, the mixture wasstirred at ambient temperature for 12 h, at which time LCMS showed thecompletion of the reaction. The reaction mixture was diluted withice-water (200 mL). The resulting precipitate was collected byfiltration, washed with water and dried.

A suspension of the above crude product in methanol (150 mL) and wasadded KOH (10.9 g, 194 mmol) in water (50 mL). The mixture was heated at50° C. for 4 h, at which time LCMS showed the completion of thereaction. Methanol was evaporated under reduced pressure, and theaqueous solution was acidified by adding 2 N HCl to pH 2. The resultingprecipitate was collected by filtration and dried to give the titlecompound (Intermediate F) (10.2 g, 91% yield) as a grey solid.

Example 1N-(2-dimethylaminoethyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To an 8 mL vial was added N,N-dimethylethane-1,2-diamine (26 mg, 0.30mmol) followed by 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylicacid (Intermediate C, 0.80 mL, 0.20 mmol, 0.25 mol/L in DMF), HATU (0.48mL, 0.24 mmol, 0.50 mol/L in DMF), and TEA (0.56 mL, 0.40 mmol). Thereaction was capped and shaken at room temperature overnight. Thereaction was then concentrated under reduced pressure and the residuewas then partitioned between dichloromethane and water. The organicphase was separated and concentrated under reduced pressure. The residuewas purified by reverse phase chromatography (0-25/ACN/0.1% NH4OH inH2O) yieldingN-(2-dimethylaminoethyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide,(21 mg, 40%). ¹H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.86-7.68 (m,2H), 7.33 (d, J=2.2 Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 3.55 (s, 3H),3.37-3.31 (m, 2H), 2.40 (t, J=6.8 Hz, 2H), 2.19 (s, 6H). LCMS M/Z (M+H)367.2.

The following compounds were prepared in a similar manner to Example 1:Examples 2-82

Example Compound Name NMR m/z 2 N-[2-(dimethylamino)-1- 1H NMR (400 MHz,DMSO) δ 12.07 (s, 1H), 277 methyl-ethyl]-6-methyl- 7.86-7.68 (m, 2H),7.33 (d, J = 2.2 Hz, 1H), 7-oxo-1H-pyrrolo[2,3- 6.70 (d, J = 2.7 Hz,1H), 3.55 (s, 3H), c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz,2H), 2.19 (s, carboxamide 6H). 3 6-methyl-N-[(1-methyl- 1H NMR (400 MHz,DMSO) δ 12.07 (s, 1H), 303 4-piperidyl)methyl]-7- 7.86-7.68 (m, 2H),7.33 (d, J = 2.2 Hz, 1H), oxo-1H-pyrrolo[2,3- 6.70 (d, J = 2.7 Hz, 1H),3.55 (s, 3H), c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H),2.19 (s, carboxamide 6H). 4 6-methyl-N-(1-methyl-4- 1H NMR (400 MHz,DMSO) δ 12.07 (s, 1H), 289 piperidyl)-7-oxo-1H- 7.86-7.68 (m, 2H), 7.33(d, J = 2.2 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 6.70 (d, J = 2.7 Hz, 1H),3.55 (s, 3H), carboxamide 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H),2.19 (s, 6H). 5 6-methyl-7-oxo-N-[2-(1- 1H NMR (400 MHz, DMSO) δ 12.09(s, 1H), 303 piperidyl)ethyl]-1H- 7.80 (s, 1H), 7.76-7.71 (m, 1H),pyrrolo[2,3-c]pyridine-4- 7.38-7.29 (m, 1H), 6.71 (s, 1H), 3.55 (s, 3H),carboxamide 3.42-3.33 (m, 2H), 2.48-2.35 (m, 6H), 1.55-1.45 (m, 4H),1.45-1.34 (m, 2H). 6 6-methyl-N-(1- 1H NMR (400 MHz, DMSO) δ 12.07 (s,1H), 275 methylpyrrolidin-3-yl)-7- 7.86-7.68 (m, 2H), 7.33 (d, J = 2.2Hz, 1H), oxo-1H-pyrrolo[2,3- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H),c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.19 (s,carboxamide 6H). 7 6-methyl-N-[2-(1- 1H NMR (400 MHz, DMSO) δ 12.07 (s,1H), 303 methylpyrrolidin-2- 7.86-7.68 (m, 2H), 7.33 (d, J = 2.2 Hz,1H), yl)ethyl]-7-oxo-1H- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H),pyrrolo[2,3-c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H),2.19 (s, carboxamide 6H). 8 6-methyl-N-(2- 1H NMR (400 MHz, DMSO) δ12.07 (s, 1H), 305 morpholinoethyl)-7-oxo- 7.86-7.68 (m, 2H), 7.33 (d, J= 2.2 Hz, 1H), 1H-pyrrolo[2,3- 6.70 (d, J = 2.7 Hz, 1H), 3.55 (s, 3H),c]pyridine-4- 3.37-3.31 (m, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.19 (s,carboxamide 6H). 9 6-but-2-enyl-N-[3-(4- ¹H NMR (400 MHz, DMSO-d₆) δ12.07 (s, 372 methylpiperazin-1- 1H), 7.93 (t, J = 5.5 Hz, 1H), 7.70 (s,1H), yl)propyl]-7-oxo-1H- 7.33 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 2.7 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 5.67-5.59 (m, 2H), 4.58-4.51 (m, 2H),carboxamide 3.27 (d, J = 7.4 Hz, 4H), 2.74-2.69 (m, 2H), 2.30 (h, J =7.8, 4.6 Hz, 6H), 2.13 (d, J = 4.3 Hz, 4H), 1.73-1.60 (m, 5H). 10tert-butyl 3-[[(6-but-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 401enyl-7-oxo-1H- 1H), 8.10 (t, J = 5.8 Hz, 1H), 7.71 (s, 1H),pyrrolo[2,3-c]pyridine-4- 7.34 (t, J = 2.6 Hz, 1H), 6.68 (dd, J = 2.8,1.5 Hz, carbonyl)amino]methyl]azetidine- 1H), 5.70-5.53 (m, 2H), 4.55(dd, J = 3.5, 1-carboxylate 1.9 Hz, 2H), 3.96-3.79 (m, 2H), 3.72-3.54(m, 2H), 3.43 (t, J = 6.3 Hz, 2H), 2.81-2.65 (m, 1H), 1.73-1.59 (m, 3H),1.36 (s, 9H). 11 6-but-2-enyl-N-[(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12(s, 343 methyl-4- 1H), 7.32 (d, J = 2.8 Hz, 1H), 7.25 (s, 1H),piperidyl)methyl]-7-oxo- 6.19 (d, J = 2.8 Hz, 1H), 5.75-5.48 (m, 2H),1H-pyrrolo[2,3- 4.62-4.46 (m, 2H), 2.82 (s, 5H), 2.12 (s, 3H),c]pyridine-4- 1.89-1.69 (m, 4H), 1.68-1.59 (m, 3H), carboxamide1.60-1.53 (m, 2H). 12 6-but-2-enyl-N-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ7.75 (t, J = 5.5 Hz, 358 methylpiperazin-1- 1H), 7.71 (s, 1H), 7.36 (d,J = 2.8 Hz, yl)ethyl]-7-oxo-1H- 1H), 6.71 (d, J = 2.8 Hz, 1H), 5.71-5.58(m, pyrrolo[2,3-c]pyridine-4- 2H), 4.56 (dd, J = 3.7, 1.7 Hz, 2H),carboxamide 3.41-3.33 (m, 6H), 2.50-2.41 (m, 2H), 2.40-2.26 (m, 4H),2.14 (s, 3H), 1.70-1.60 (m, 3H). 13 benzyl N-[2-[[6-[(E)-but- ¹H NMR(400 MHz, DMSO-d₆) δ 12.06 (s, 409 2-enyl]-7-oxo-1H- 1H), 7.98 (t, J =5.7 Hz, 1H), 7.73 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.38-7.25 (m, 7H),6.75-6.69 (m, 1H), carbonyl]amino]ethyl]carbamate 5.67-5.59 (m, 2H),5.02 (s, 2H), 4.57-4.50 (m, 2H), 3.32-3.27 (m, 2H), 3.23-3.14 (m, 2H),1.68-1.62 (m, 3H). 14 N-(2-acetamidoethyl)-6- ¹H NMR (400 MHz, DMSO-d₆)δ 12.07 (s, 317 but-2-enyl-7-oxo-1H- 1H), 8.05-7.91 (m, 2H), 7.73 (s,1H), pyrrolo[2,3-c]pyridine-4- 7.39-7.31 (m, 1H), 6.81-6.65 (m, 1H),carboxamide 5.81-5.50 (m, 2H), 4.64-4.46 (m, 3H), 3.36-3.27 (m, 2H),3.25-3.13 (m, 2H), 1.81 (s, 3H), 1.72-1.55 (m, 4H). 156-but-2-enyl-N-tert- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 288butyl-7-oxo-1H- 1H), 7.68 (s, 1H), 7.43-7.15 (m, 2H),pyrrolo[2,3-c]pyridine-4- 6.63 (d, J = 2.7 Hz, 1H), 5.70-5.44 (m, 2H),carboxamide 4.54 (dd, J = 3.9, 2.0 Hz, 2H), 1.73-1.59 (m, 3H), 1.38 (s,10H). 16 N-[2-(4-benzylpiperazin- ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s,434 1-yl)ethyl]-6-but-2-enyl- 1H), 7.73 (d, J = 18.6 Hz, 2H), 7.38-7.19(m, 7-oxo-1H-pyrrolo[2,3- 7H), 6.70 (d, J = 2.8 Hz, 1H), 5.69-5.59 (m,c]pyridine-4- 2H), 4.58-4.52 (m, 2H), 3.45 (s, 2H), carboxamide3.40-3.31 (m, 2H), 2.58-2.28 (m, 10H), 1.69-1.62 (m, 3H). 17 benzylN-[3-[(6-but-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 423 enyl-7-oxo-1H-1H), 7.91 (t, J = 5.7 Hz, 1H), 7.72 (s, 1H), pyrrolo[2,3-c]pyridine-4-7.41-7.22 (m, 7H), 6.71 (d, J = 2.8 Hz, 1H),carbonyl)amino]propyl]carbamate 5.71-5.59 (m, 2H), 5.02 (s, 2H), 4.55(d, J = 4.9 Hz, 2H), 3.31-3.21 (m, 2H), 3.12-3.02 (m, 2H), 1.72-1.61 (m,5H). 18 6-but-2-enyl-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 328methylcyclohexyl)-7- 1H), 7.66 (s, 1H), 7.34 (d, J = 2.7 Hz, 1H),oxo-1H-pyrrolo[2,3- 6.99 (s, 1H), 6.60 (d, J = 2.7 Hz, 1H),c]pyridine-4- 5.78-5.52 (m, 2H), 4.62-4.49 (m, 2H), carboxamide2.28-2.11 (m, 2H), 1.72-1.62 (m, 3H), 1.56-1.44 (m, 4H), 1.44-1.17 (m,7H). 19 benzyl 3-[2-[(6-but-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 463enyl-7-oxo-1H- 1H), 7.96 (s, 1H), 7.71 (d, J = 3.0 Hz, 1H),pyrrolo[2,3-c]pyridine-4- 7.50-7.18 (m, 7H), 6.71 (d, J = 2.7 Hz, 1H),carbonyl)amino]ethyl]pyrrolidine- 5.74-5.53 (m, 2H), 5.06 (s, 2H), 4.54(s, 2H), 1-carboxylate 3.69-3.51 (m, 1H), 3.52-3.36 (m, 1H), 3.32-3.14(m, 2H), 3.00-2.84 (m, 1H), 2.27-2.13 (m, 1H), 2.13-1.97 (m, 1H),1.70-1.40 (m, 7H). 20 6-methyl-7-oxo-N-[2-[1- 1H NMR (400 MHz, DMSO-d6)δ 12.07 (s, 385 (2,2,2-trifluoroethyl)-4- 1H), 7.90 (t, J = 5.6 Hz, 1H),7.79 (s, 1H), piperidyl]ethyl]-1H- 7.31 (t, J = 2.5 Hz, 1H), 6.69 (dd, J= 2.9, 1.5 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.32-3.22(m, 2H), carboxamide 3.11 (q, J = 10.3 Hz, 2H), 2.89 (dt, J = 12.0, 3.4Hz, 2H), 2.28 (dd, J = 12.8, 10.1 Hz, 2H), 1.66 (dd, J = 11.8, 3.6 Hz,2H), 1.45 (q, J = 7.1 Hz, 2H), 1.35-1.24 (m, 1H), 1.17 (qd, J = 11.9,3.8 Hz, 2H). 21 N-[4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 317(dimethylamino)cyclohexyl]- 1H), 7.86-7.76 (m, 1H), 7.75-7.63 (m, 1H),6-methyl-7-oxo-1H- 7.30 (d, J = 2.7 Hz, 1H), 6.68 (d, J = 2.7 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 3.95-3.62 (m, 1H), 3.54 (s, 3H), 2.17 (s,carboxamide 6H), 2.14-1.97 (m, 1H), 1.95-1.87 (m, 1H), 1.86-1.67 (m,3H), 1.59-1.42 (m, 2H), 1.36-1.21 (m, 2H). 22 N-(1-benzylpyrrolidin-3-¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 365 yl)-N,6-dimethyl-7-oxo- 1H),7.36-7.27 (m, 6H), 7.27-7.19 (m, 1H), 1H-pyrrolo[2,3- 6.19-6.13 (m, 1H),4.69 (s, 1H), 3.60 (d, J = 13.1 Hz, c]pyridine-4- 1H), 3.54-3.44 (m,4H), 2.94 (s, carboxamide 3H), 2.82-2.71 (m, 1H), 2.71-2.63 (m, 1H),2.42 (t, J = 9.2 Hz, 1H), 2.22 (q, J = 8.2 Hz, 1H), 2.07-1.99 (m, 1H),1.90-1.76 (m, 1H). 23 N-[(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 331isopropylpyrrolidin-3- 1H), 7.39 (s, 1H), 7.32 (d, J = 2.8 Hz, 1H),yl)methyl]-N,6-dimethyl- 6.18 (d, J = 2.8 Hz, 1H), 3.53 (s, 3H),7-oxo-1H-pyrrolo[2,3- 3.44-3.36 (m, 2H), 2.94 (s, 3H), 2.47-2.34 (m,c]pyridine-4- 3H), 2.29-2.16 (m, 2H), 1.87-1.75 (m, 1H), carboxamide1.36-1.25 (m, 1H), 1.02-0.90 (m, 7H). 24 6-methyl-N-[(1-methyl- ¹H NMR(400 MHz, DMSO-d₆) δ 12.04 (s, 303 3-piperidyl)methyl]-7- 1H), 7.93 (t,J = 5.8 Hz, 1H), 7.82 (s, 1H), oxo-1H-pyrrolo[2,3- 7.34-7.28 (m, 1H),6.73-6.67 (m, 1H), c]pyridine-4- 3.55 (s, 3H), 3.21-3.04 (m, 2H),2.76-2.67 (m, carboxamide 1H), 2.65-2.57 (m, 1H), 2.13 (s, 3H),1.88-1.74 (m, 2H), 1.71-1.57 (m, 3H), 1.50-1.37 (m, 1H), 0.98-0.85 (m,1H). 25 6-methyl-N-[2-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 317methyl-4- 1H), 7.88 (t, J = 5.6 Hz, 1H), 7.78 (s, 1H),piperidyl)ethyl]-7-oxo- 7.31 (t, J = 2.7 Hz, 1H), 6.69 (t, J = 2.3 Hz,1H-pyrrolo[2,3- 1H), 3.55 (s, 3H), 3.32-3.22 (m, 2H), c]pyridine-4-2.76-2.67 (m, 2H), 2.12 (s, 3H), 1.85-1.74 (m, carboxamide 2H),1.70-1.61 (m, 2H), 1.50-1.40 (m, 2H), 1.33-1.08 (m, 3H). 266-methyl-N-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 317 methyl-1-1H), 7.80 (s, 1H), 7.75 (t, J = 5.6 Hz, 1H), piperidyl)ethyl]-7-oxo-7.34 (t, J = 2.6 Hz, 1H), 6.73-6.67 (m, 1H), 1H-pyrrolo[2,3- 3.55 (s,3H), 3.40-3.30 (m, 2H), c]pyridine-4- 2.90-2.81 (m, 2H), 2.44 (t, J =6.9 Hz, 2H), carboxamide 2.00-1.88 (m, 2H), 1.62-1.53 (m, 2H), 1.39-1.27(m, 1H), 1.20-1.06 (m, 2H), 0.89 (d, J = 6.4 Hz, 3H). 27N-[(1-ethylpyrrolidin-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 317yl)methyl]-N,6-dimethyl- 1H), 7.39 (s, 1H), 7.32 (d, J = 2.8 Hz, 1H),7-oxo-1H-pyirolo[2,3- 6.18 (d, J = 2.7 Hz, 1H), 3.53 (s, 3H),c]pyridine-4- 3.43-3.36 (m, 2H), 2.94 (s, 3H), 2.41-2.29 (m, carboxamide1H), 2.19 (s, 1H), 1.83 (s, 1H), 1.31 (s, 1H), 1.03-0.90 (m, 4H). 286-methyl-4-(7-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 301 2,7-1H), 7.58 (s, 1H), 7.31 (d, J = 2.7 Hz, 1H), diazaspiro[3.4]octane-2-6.55 (d, J = 2.7 Hz, 1H), 4.06 (s, 4H), 3.55 (s, carbonyl)-1H- 3H), 2.63(s, 2H), 2.44 (t, J = 7.1 Hz, 2H), pyrrolo[2,3-c]pyridin-7- 2.22 (s,3H), 2.02 (t, J = 7.1 Hz, 2H). one 29 6-methyl-N-[3-(2- ¹H NMR (400 MHz,DMSO-d₆) δ 12.06 (s, 331 methyl-1- 1H), 7.94 (t, J = 5.6 Hz, 1H), 7.78(s, 1H), piperidyl)propyl]-7-oxo- 7.32 (d, 1H), 6.69 (d, J = 2.7 Hz,1H), 3.55 (s, 1H-pyrrolo[2,3- 3H), 3.30-3.19 (m, 2H), 2.83-2.62 (m, 2H),c]pyridine-4- 2.31-2.19 (m, 2H), 2.10-1.99 (m, 1H), carboxamide1.70-1.46 (m, 5H), 1.46-1.31 (m, 1H), 1.30-1.10 (m, 2H), 0.98 (d, J =6.2 Hz, 3H). 30 N-[2-(4-hydroxy-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s,319 piperidyl)ethyl]-6- 1H), 7.79 (s, 1H), 7.75 (t, J = 5.5 Hz, 1H),methyl-7-oxo-1H- 7.34 (d, J = 2.8 Hz, 1H), 6.70 (d, J = 2.8 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 4.51 (d, J = 4.1 Hz, 1H), 3.55 (s, 3H),carboxamide 3.49-3.38 (m, 1H), 3.38-3.30 (m, 2H), 2.80-2.70 (m, 2H),2.44 (t, J = 6.9 Hz, 2H), 2.13-2.02 (m, 2H), 1.76-1.65 (m, 2H),1.46-1.32 (m, 2H). 31 6-methyl-N-(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06(s, 319 morpholinopropyl)-7- 1H), 7.94 (t, J = 5.5 Hz, 1H), 7.79 (s,1H), oxo-1H-pyrrolo[2,3- 7.32 (d, J = 2.7 Hz, 1H), 6.70 (d, J = 2.7 Hz,c]pyridine-4- 1H), 3.59-3.52 (m, 7H), 3.31-3.23 (m, 2H), carboxamide2.39-2.29 (m, 6H), 1.68 (p, J = 7.1 Hz, 2H). 32 6-methyl-N-[2-(4- ¹H NMR(400 MHz, DMSO-d₆) δ 12.09 (s, 318 methylpiperazin-1- 1H), 7.79 (s, 1H),7.76 (t, J = 5.5 Hz, 1H), yl)ethyl]-7-oxo-1H- 7.34 (d, J = 2.7 Hz, 1H),6.71 (d, J = 2.8 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H),3.41-3.32 (m, 2H), carboxamide 2.49-2.42 (m, 3H), 2.32 (s, 6H), 2.15 (s,3H). 33 N-[2-(3.5-dimethyl-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 331piperidyl)ethyl]-6- 1H), 7.79 (s, 1H), 7.75 (t, J = 5.5 Hz, 1H),methyl-7-oxo-1H- 7.34 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 2.7 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.36 (q, J = 6.5 Hz, 2H),carboxamide 2.88-2.80 (m, 2H), 2.44 (t, J = 6.9 Hz, 2H), 1.71-1.52 (m,3H), 1.46 (t, J = 10.8 Hz, 2H), 0.82 (d, J = 6.4 Hz, 6H), 0.49 (q, J =11.7 Hz, 1H). 34 6-methyl-N-[3-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s,332 methylpiperazin-1- 1H), 7.94 (t, J = 5.5 Hz, 1H), 7.79 (s, 1H),yl)propyl]-7-oxo-1H- 7.32 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 2.7 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.31-3.22 (m, 2H),carboxamide 2.38-2.26 (m, 10H), 2.12 (s, 3H), 1.66 (p, J = 7.0 Hz, 2H).35 N-(1,1-dimethyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 333morpholino-ethyl)-6- 1H), 7.74 (s, 1H), 7.37-7.31 (m, 1H), 7.22 (s,methyl-7-oxo-1H- 1H), 6.65 (d, J = 2.7 Hz, 1H), 3.59-3.51 (m,pyrrolo[2,3-c]pyridine-4- 7H), 2.62 (s, 2H), 2.55-2.49 (m, 2H), 1.36 (s,carboxamide 6H). 36 6-methyl-N-(2-methyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ12.20 (s, 333 morpholino-propyl)-7- 1H), 7.81 (s, 1H), 7.42 (d, J = 2.8Hz, 1H), oxo-1H-pyrrolo [2,3- 7.34 (t, J = 5.5 Hz, 1H), 6.72 (d, J = 2.8Hz, c]pyridine-4- 1H), 3.58 (d, J = 5.9 Hz, 7H), 3.31 (s, 1H),carboxamide 2.53 (t, J = 4.5 Hz, 4H), 1.02 (s, 6H). 37N-[2-(1,1-dioxo-1,4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 353thiazinan-4-yl)ethyl]-6- 1H), 7.85 (t, J = 5.7 Hz, 1H), 7.79 (s, 1H),methyl-7-oxo-1H- 7.33 (d, J = 2.8 Hz, 1H), 6.70 (d, J = 2.7 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 3.55 (s, 3H), 3.37 (q, J = 6.3 Hz, 2H),carboxamide 3.12-3.04 (m, 4H), 3.01-2.94 (m, 4H), 2.67 (t, J = 6.6 Hz,2H). 38 6-methyl-4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 275methylpiperazine-1- 1H), 7.42 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H),carbonyl)-1H- 6.26 (d, J = 2.8 Hz, 1H), 3.53 (s, 3H),pyrrolo[2,3-c]pyridin-7- 3.51-3.44 (m, 4H), 2.30 (t, J = 5.0 Hz, 4H),2.19 (s, one 3H). 39 N,6-dimethyl-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ12.11 (s, 303 methyl-4-piperidyl)-7- 1H), 7.36 (s, 1H), 7.31 (d, J = 2.6Hz, 1H), oxo-1H-pyrrolo[2,3- 6.18 (d, J = 2.7 Hz, 1H), 3.95 (s, 1H),3.52 (s, c]pyridine-4- 3H), 2.84-2.76 (m, 5H), 2.12 (s, 3H), carboxamide1.85-1.73 (m, 4H), 1.61-1.54 (m, 2H). 40 4-[4- ¹H NMR (400 MHz, DMSO-d₆)δ 12.12 (s, 303 (dimethylamino)piperidine- 1H), 7.41 (s, 1H), 7.33 (d, J= 2.8 Hz, 1H), 1-carbonyl]-6-methyl- 6.24 (d, J = 2.8 Hz, 1H), 4.04 (s,2H), 3.53 (s, 1H-pyrrolo[2,3- 3H), 2.97-2.86 (m, 2H), 2.36-2.24 (m, 1H),c]pyridin-7-one 2.16 (s, 6H), 1.75 (d, J = 12.2 Hz, 2H), 1.38-1.23 (m,2H). 41 N-(1-isopropyl-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 331piperidyl)-N,6-dimethyl- 1H), 7.36 (s, 1H), 7.32 (t, J = 2.7 Hz, 1H),7-oxo-1H-pyrrolo[2,3- 6.21-6.15 (m, 1H), 3.93 (s, 1H), 3.52 (s, 3H),c]pyridine-4- 2.85-2.77 (m, 5H), 2.66 (p, J = 6.6 Hz, 1H), carboxamide2.10-2.02 (m, 2H), 1.81-1.66 (m, 2H), 1.65-1.57 (m, 2H), 0.92 (d, J =6.5 Hz, 6H). 42 6-methyl-7-oxo-N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ12.03 (s, 352 pyridyl)-4-piperidyl]-1H- 1H), 8.14-8.07 (m, 1H),7.84-7.77 (m, 2H), pyrrolo[2,3-c]pyridine-4- 7.57-7.47 (m, 1H), 7.30 (t,J = 2.7 Hz, 1H), carboxamide 6.87 (d, J = 8.6 Hz, 1H), 6.70 (t, J = 2.4Hz, 1H), 6.64-6.56 (m, 1H), 4.33-4.24 (m, 2H), 4.13-3.98 (m, 1H), 3.54(s, 3H), 3.02-2.89 (m, 2H), 1.91-1.82 (m, 2H), 1.59-1.44 (m, 2H). 43N-(1-cyclopentyl-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 343piperidyl)-6-methyl-7- 1H), 7.80 (s, 1H), 7.30 (t, J = 2.8 Hz, 1H),oxo-1H-pyrrolo[2,3- 6.68 (t, J = 2.4 Hz, 1H), 3.72 (s, 1H), 3.55 (s,c]pyridine-4- 3H), 3.28 (s, 2H), 2.98-2.93 (m, 2H), carboxamide1.84-1.79 (m, 4H), 1.63-1.58 (m, 2H), 1.56-1.46 (m, 3H), 1.38-1.33 (m,2H). 44 6-methyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 353pyrimidin-2-yl-4- 1H), 8.36 (d, J = 4.7 Hz, 2H), 7.84-7.77 (m,piperidyl)-1H- 2H), 7.30 (t, J = 2.7 Hz, 1H), 6.70 (t, J = 2.4 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 6.60 (t, J = 4.7 Hz, 1H), carboxamide4.67-4.57 (m, 2H), 4.16-4.01 (m, 1H), 3.54 (s, 3H), 3.12-3.00 (m, 2H),1.93-1.84 (m, 2H), 1.54-1.39 (m, 2H). 45 6-methyl-N-[2-(3- ¹H NMR (400MHz, DMSO-d₆) δ 12.09 (s, 317 methyl-1- 1H), 7.79 (s, 1H), 7.74 (t, J =5.5 Hz, 1H), piperidyl)ethyl]-7-oxo- 7.34 (d, J = 2.8 Hz, 1H), 6.70 (d,J = 2.8 Hz, 1H-pyrrolo[2,3- 1H), 3.55 (s, 3H), 3.41-3.31 (m, 2H),c]pyridine-4- 2.85-2.76 (m, 2H), 2.43 (t, J = 6.9 Hz, 2H), carboxamide1.94-1.83 (m, 1H), 1.69-1.38 (m, 6H), 0.84 (d, J = 6.1 Hz, 3H). 466-methyl-4-[4-(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 351.18pyridylmethyl)piperidine- 1H), 8.50-8.34 (m, 2H), 7.64-7.55 (m, 1H),1-carbonyl]-1H- 7.39 (s, 1H), 7.37-7.25 (m, 2H), 6.24 (d, J = 2.8 Hz,pyrrolo[2,3-c]pyridin-7- 1H), 4.32-3.84 (m, 2H), 3.53 (s, 3H), one 2.85(t, J = 12.2 Hz, 2H), 2.55 (d, J = 7.1 Hz, 2H), 1.87-1.70 (m, 1H), 1.57(d, J = 12.8 Hz, 2H), 1.23-1.03 (m, 2H). 47 4-(4-tert-butylpiperidine-¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (s, 316.2 1-carbonyl)-6-methyl- 1H),7.32 (d, J = 2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H-pyrrolo[2,3- 1H), 4.11(d, J = 16.3 Hz, 2H), 3.52 (s, c]pyridin-7-one 3H), 2.90-2.82 (m, 2H),1.81-1.58 (m, 2H), 1.33-1.17 (m, 1H), 1.17-1.01 (m, 2H), 0.84 (s, 9H),0.81 (d, J = 2.8 Hz, 1H). 48 4-[4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15(s, 370.13 chlorophenyl)piperidine- 1H), 7.46 (s, 1H), 7.39-7.27 (m,5H), 1-carbonyl]-6-methyl- 6.35-6.28 (m, 1H), 4.19 (s, 2H), 3.54 (s,3H), 1H-pyrrolo[2,3- 3.00 (t, J = 12.7 Hz, 2H), 2.88-2.75 (m, 1H),c]pyridin-7-one 1.78 (d, J = 12.7 Hz, 2H), 1.64-1.48 (m, 2H). 494-[4-(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 354.16fluorophenyl)piperidine- 1H), 7.46 (s, 1H), 7.40-7.29 (m, 2H),1-carbonyl]-6-methyl- 7.17-7.10 (m, 2H), 7.07-6.98 (m, 1H), 6.34 (d, J =2.8 Hz, 1H-pyrrolo[2,3- 1H), 4.20 (s, 2H), 3.54 (s, 3H), c]pyridin-7-one3.08-2.93 (m, 2H), 2.89 (t, J = 5.6 Hz, 1H), 1.80 (d, J = 13.2 Hz, 2H),1.68-1.51 (m, 2H). 50 4-[4-(benzimidazol-1- ¹H NMR (400 MHz, DMSO-d₆) δ12.18 (s, 376.18 yl)piperidine-1- 1H), 8.39 (s, 1H), 7.74-7.61 (m, 2H),7.50 (s, carbonyl]-6-methyl-1H- 1H), 7.36 (d, J = 2.8 Hz, 1H), 7.32-7.16(m, pyrrolo[2,3-c]pyridin-7- 2H), 6.39 (d, J = 2.8 Hz, 1H), 4.77-4.63(m, one 1H), 4.29 (d, J = 15.4 Hz, 2H), 3.56 (s, 3H), 3.17 (t, J = 12.7Hz, 2H), 2.20-1.89 (m, 4H). 51 6-methyl-4-(4-pyrazin-2- ¹H NMR (400 MHz,DMSO-d₆) δ 12.15 (s, 338.16 ylpiperidine-1-carbonyl)- 1H), 8.64 (d, J =1.5 Hz, 1H), 8.61-8.56 (m, 1H-pyrrolo[2,3- 1H), 8.50 (d, J = 2.5 Hz,1H), 7.46 (s, 1H), c]pyridin-7-one 7.35 (t, J = 2.6 Hz, 1H), 6.33-6.28(m, 1H), 4.20 (s, 2H), 3.54 (s, 3H), 3.15-2.99 (m, 3H), 1.89 (d, J =12.8 Hz, 2H), 1.79-1.60 (m, 2H). 52 4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ12.14 (s, 371.24 [cyclohexyl(methyl)amino]piperidine- 1H), 7.42 (s, 1H),7.38-7.29 (m, 1H), 1-carbonyl]- 6.24 (d, J = 2.8 Hz, 1H), 4.27-3.88 (m,2H), 6-methyl-1H- 3.53 (d, J = 2.2 Hz, 3H), 2.95-2.84 (m, 2H),pyrrolo[2,3-c]pyridin-7- 2.75-2.65 (m, 1H), 2.14 (d, J = 5.0 Hz, 3H),one 1.69 (d, J = 18.6 Hz, 6H), 1.55 (d, J = 12.3 Hz, 2H), 1.44-1.31 (m,1H), 1.30-1.12 (m, 4H), 1.05 (s, 2H). 53 4-(4-fluoropiperidine-1- ¹H NMR(400 MHz, DMSO-d₆) δ 12.21 (d, J = 46.1 Hz, 278.13carbonyl)-6-methyl-1H- 1H), 7.56-7.18 (m, 2H), 6.28 (d, J = 2.8 Hz,pyrrolo[2,3-c]pyridin-7- 1H), 5.07-4.68 (m, 1H), 3.59 (d, J = 9.9 Hz,one 2H), 3.53 (s, 3H), 3.51-3.43 (m, 2H), 1.98-1.78 (m, 2H), 1.78-1.60(m, 2H). 54 N-[2-[1-(6-methyl-7-oxo- ¹H NMR (400 MHz, DMSO-d₆) δ 7.39(s, 381.16 1H-pyrrolo[2,3- 1H), 7.33 (d, J = 2.8 Hz, 1H), 6.25 (d, J =2.7 Hz, c]pyridine-4-carbonyl)-4- 1H), 4.06 (s, 2H), 3.53 (s, 3H),piperidyl]ethyl]methanesulfonamide 3.15-3.05 (m, 1H), 3.03-2.92 (m, 4H),1.80-1.58 (m, 5H), 1.48-1.37 (m, 3H), 1.13-1.02 (m, 2H). 556-methyl-4-[4-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 337.17pyridyl)piperidine-1- 1H), 8.55-8.46 (m, 1H), 7.77-7.68 (m, 1H),carbonyl]-1H- 7.46 (d, J = 1.2 Hz, 1H), 7.37-7.26 (m, 2H),pyrrolo[2,3-c]pyridin-7- 7.26-7.19 (m, 1H), 6.32-6.28 (m, 1H), one 4.18(s, 2H), 3.54 (d, J = 1.2 Hz, 3H), 3.11-2.92 (m, 3H), 1.92-1.79 (m, 2H),1.77-1.61 (m, 2H). 56 6-methyl-4-(4-pyrimidin- ¹H NMR (400 MHz, DMSO-d₆)δ 12.16 (s, 338.16 4-ylpiperidine-1- 1H), 9.21-9.00 (m, 1H), 8.86-8.61(m, 1H), carbonyl)-1H- 7.51-7.44 (m, 2H), 7.35 (d, J = 2.7 Hz, 1H),pyrrolo[2,3-c]pyridin-7- 6.29 (d, J = 2.7 Hz, 1H), 4.19 (s, 2H), 3.54(s, one 2H), 3.11-2.92 (m, 3H), 2.92-2.82 (m, 1H), 1.96-1.83 (m, 2H),1.77-1.59 (m, 2H). 57 6-methyl-4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.16(s, 328.13 (trifluoromethyl)piperidine- 1H), 7.47 (s, 1H), 7.34 (d, J =2.8 Hz, 1H), 1-carbonyl]-1H- 6.25 (d, J = 2.8 Hz, 1H), 4.15 (s, 2H),3.53 (s, pyrrolo[2,3-c]pyridin-7- 3H), 2.95 (t, J = 13.2 Hz, 2H),2.70-2.57 (m, one 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.48-1.29 (m, 2H). 586-methyl-4-[4-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 351.2pyridylmethyl)piperidine- 1H), 8.52-8.43 (m, 1H), 7.73-7.62 (m, 1H),1-carbonyl]-1H- 7.39 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H),pyrrolo[2,3-c]pyridin-7- 7.27-7.13 (m, 2H), 6.24 (d, J = 2.7 Hz, 1H),4.02 (s, one 2H), 3.52 (s, 3H), 2.88 (d, J = 12.3 Hz, 2H), 2.68 (d, J =7.1 Hz, 2H), 2.43-2.30 (m, 0H), 2.15-1.88 (m, 1H), 1.57 (d, J = 12.8 Hz,2H), 1.27-1.09 (m, 2H). 59 6-methyl-4-[4-(1- ¹H NMR (400 MHz, DMSO-d₆) δ12.13 (s, 343.2 piperidyl)piperidine-1- 1H), 7.41 (s, 1H), 7.35-7.31 (m,1H), carbonyl]-1H- 6.24 (d, J = 2.7 Hz, 1H), 4.06 (s, 2H), 3.53 (s, 3H),pyrrolo[2,3-c]pyridin-7- 2.85 (d, J = 11.6 Hz, 2H), 2.46-2.36 (m, 5H),one 1.72 (d, J = 12.3 Hz, 2H), 1.47 (t, J = 5.5 Hz, 4H), 1.41-1.32 (m,4H). 60 4-[3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 289.2(dimethylamino)pyrrolidine- 1H), 7.52 (s, 1H), 7.31 (d, J = 2.8 Hz, 1H),1-carbonyl]-6-methyl- 6.33 (d, J = 2.7 Hz, 1H), 3.53 (s, 3H), 3.33 (s,1H-pyrrolo[2,3- 1H), 2.87 (s, 3H), 2.77-2.55 (m, 1H), c]pyridin-7-one2.17-1.95 (m, 7H), 1.89-1.65 (m, 1H). 61 6-methyl-4-[4-(4- ¹H NMR (400MHz, DMSO-d₆) δ 12.13 (s, 358.2 methylpiperazin-1- 1H), 7.41 (s, 1H),7.33 (d, J = 2.8 Hz, 1H), yl)piperidine-1- 6.24 (d, J = 2.8 Hz, 1H),4.05 (s, 2H), 3.53 (s, carbonyl]-1H- 4H), 2.97-2.80 (m, 4H), 2.35-2.18(m, 4H), pyrrolo[2,3-c]pyridin-7- 2.13 (d, J = 4.6 Hz, 5H), 1.81-1.70(m, 2H), one 1.42-1.23 (m, 2H). 62 6-methyl-4-[4-(4-methyl- ¹H NMR (400MHz, DMSO-d₆) δ 12.15 (s, 357.2 1-piperidyl)piperidine-1- 1H), 7.40 (s,1H), 7.32 (d, J = 2.8 Hz, 1H), carbonyl]-1H- 6.23 (d, J = 2.8 Hz, 1H),3.52 (s, 3H), pyrrolo[2,3-c]pyridin-7- 3.00-2.72 (m, 6H), 2.49-2.39 (m,2H), one 2.17-2.01 (m, 2H), 1.86-1.64 (m, 2H), 1.64-1.50 (m, 2H),1.47-1.17 (m, 2H), 1.17-0.96 (m, 2H), 0.96-0.79 (m, 3H). 636-methyl-4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 345.2morpholinopiperidine-1- 1H), 7.42 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H),carbonyl)-1H- 2.47-2.46 (m, 0H), 6.25 (d, J = 2.7 Hz, 1H),pyrrolo[2,3-c]pyridin-7- 4.08 (d, J = 16.5 Hz, 2H), 3.54 (d, J = 11.3Hz, one 8H), 3.01-2.81 (m, 3H), 2.45 (d, J = 4.7 Hz, 3H), 1.79 (d, J =12.5 Hz, 2H), 1.32 (q, J = 14.3, 12.7 Hz, 2H). 64 1-(6-methyl-7-oxo-1H-¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 285.2 pyrrolo[2,3-c]pyridine-4-1H), 7.45 (s, 1H), 7.34 (d, J = 2.1 Hz, 1H), carbonyl)piperidine-4- 6.29(d, J = 2.7 Hz, 1H), 3.70 (s, 2H), 3.53 (s, carbonitrile 3H), 3.32 (s,2H), 3.13 (m, J = 8.7, 4.5 Hz, 1H), 1.97-1.83 (m, 2H), 1.71 (m, J =13.7, 9.2, 4.5 Hz, 2H). 65 6-methyl-4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ7.38 (s, 274.2 methylpiperidine-1- 1H), 7.32 (d, J = 2.7 Hz, 1H), 6.23(d, J = 2.7 Hz, carbonyl)-1H- 1H), 3.52 (s, 3H), 2.95-2.82 (m, 4H),pyrrolo[2,3-c]pyridin-7- 1.72-1.54 (m, 4H), 1.12-0.98 (m, 2H), one 0.91(d, J = 6.0 Hz, 3H). 66 4-(4-methoxypiperidine- ¹H NMR (400 MHz,DMSO-d₆) δ 12.14 (s, 290.2 1-carbonyl)-6-methyl- 1H), 7.42 (s, 1H),7.36-7.30 (m, 1H), 1H-pyrrolo[2,3- 6.25 (d, J = 2.7 Hz, 1H), 3.71 (d, J= 10.6 Hz, 2H), c]pyridin-7-one 3.53 (s, 3H), 3.47-3.36 (m, 1H), 3.25(s, 3H), 3.25-3.17 (m, 2H), 1.88-1.78 (m, 2H), 1.48-1.34 (m, 2H). 676-methyl-4-[4-(3-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 357.21-piperidyl)piperidine-1- 1H), 7.32 (d, J = 2.7 Hz, 1H), 6.23 (d, J =2.7 Hz, carbonyl]-1H- 1H), 4.06 (s, 2H), 3.52 (s, 3H), 2.86 (d, J = 4.2Hz, pyrrolo[2,3-c]pyridin-7- 2H), 2.80-2.69 (m, 3H), one 2.12-1.95 (m,2H), 1.84-1.67 (m, 4H), 1.44-1.29 (m, 4H), 0.89-0.76 (m, 5H). 684-[4-(1-hydroxy-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 318.2methyl-ethyl)piperidine- 1H), 7.40 (s, 1H), 7.33 (d, J = 2.7 Hz, 1H),1-carbonyl]-6-methyl- 6.23 (d, J = 2.8 Hz, 1H), 4.14 (s, 2H), 3.53 (s,1H-pyrrolo[2,3- 3H), 2.95-2.85 (m, 1H), 2.84-2.71 (m, 2H),c]pyridin-7-one 1.81-1.61 (m, 2H), 1.50-1.34 (m, 1H), 1.22-1.08 (m, 2H),1.03 (s, 6H). 69 4-[4-[(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 368.2fluorophenyl)methyl]piperidine- 1H), 7.39 (s, 1H), 7.33 (d, J = 2.8 Hz,1H), 1-carbonyl]-6- 7.20 (m, J = 9.1, 5.7, 2.8 Hz, 2H),methyl-1H-pyrrolo[2,3- 7.14-7.04 (m, 2H), 6.24 (d, J = 2.7 Hz, 1H), 4.02(s, c]pyridin-7-one 2H), 3.52 (s, 3H), 2.84 (t, J = 12.7 Hz, 2H), 2.53(s, 2H), 1.74 (m, J = 11.3, 4.9 Hz, 1H), 1.57 (d, J = 13.0 Hz, 2H), 1.13(m, J = 13.6, 6.7 Hz, 2H). 70 6-methyl-4-(piperidine-1- ¹H NMR (400 MHz,DMSO-d₆) δ 12.14 (s, 260.2 carbonyl)-1H- 1H), 7.39 (s, 1H), 7.33 (d, J =2.8 Hz, 1H), pyrrolo[2,3-c]pyridin-7- 6.24 (d, J = 2.7 Hz, 1H), 3.53 (s,3H), 3.44 (t, one J = 5.3 Hz, 2H), 2.88 (d, J = 10.4 Hz, 2H), 1.76-1.55(m, 2H), 1.55-1.37 (m, 4H). 71 6-methyl-4-(4- ¹H NMR (400 MHz, DMSO-d₆)δ 12.15 (s, 336.2 phenylpiperidine-1- 1H), 7.46 (s, 1H), 7.35 (d, J =2.8 Hz, 1H), carbonyl)-1H- 7.33-7.24 (m, 4H), 7.24-7.16 (m, 1H),pyrrolo[2,3-c]pyridin-7- 6.32 (d, J = 2.7 Hz, 1H), 4.20 (s, 2H), 3.54(s, 3H), one 3.01 (t, J = 12.6 Hz, 2H), 2.87-2.73 (m, 1H), 1.79 (d, J =12.8 Hz, 2H), 1.68-1.47 (m, 2H). 72 4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ12.15 (s, 304.2 (methoxymethyl)piperidine- 1H), 7.39 (s, 1H), 7.33 (d, J= 2.7 Hz, 1H), 1-carbonyl]-6-methyl- 6.24 (d, J = 2.7 Hz, 1H), 4.05 (s,2H), 3.53 (s, 1H-pyrrolo[2,3- 3H), 3.24 (d, J = 7.3 Hz, 4H), 3.19 (d, J= 6.3 Hz, c]pyridin-7-one 2H), 2.88-2.77 (m, 2H), 1.66 (d, J = 12.8 Hz,2H), 1.21-1.00 (m, 2H). 73 6-methyl-4-(2-oxa-7- ¹H NMR (400 MHz,DMSO-d₆) δ 12.15 (s, 302.1 azaspiro[3.5]nonane-7- 1H), 7.40 (s, 1H),7.33 (d, J = 2.8 Hz, 1H), carbonyl)-1H- 6.25 (d, J = 2.8 Hz, 1H), 4.33(s, 4H), 3.52 (s, pyrrolo[2,3-c]pyridin-7- 3H), 3.40 (t, J = 5.7 Hz,4H), 1.83-1.72 (m, one 4H). 74 N,N-dimethyl-1-(6- ¹H NMR (400 MHz,DMSO-d₆) δ 12.15 (s, 331.2 methyl-7-oxo-1H- 1H), 7.43 (s, 1H), 7.34 (t,J = 2.2 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 6.23 (d, J = 2.7 Hz, 1H),4.07 (s, 2H), 3.53 (s, carbonyl)piperidine-4- 3H), 3.08-2.71 (m, 7H),2.64 (d, J = 8.0 Hz, carboxamide 2H), 1.64 (t, J = 8.0 Hz, 2H),1.57-1.35 (m, 2H), 1.10 (s, 0H). 75 4-[4- ¹H NMR (400 MHz, DMSO-d₆) δ12.14 (s, 290.2 (hydroxymethyl)piperidine- 1H), 7.40 (s, 1H), 7.33 (d, J= 2.8 Hz, 1H), 1-carbonyl]-6-methyl- 6.24 (d, J = 2.7 Hz, 1H), 4.49 (d,J = 5.7 Hz, 1H-pyrrolo[2,3- 1H), 4.06 (s, 2H), 3.53 (s, 3H), 3.28-3.17(m, c]pyridin-7-one 2H), 2.92-2.81 (m, 2H), 1.76-1.53 (m, 3H), 1.17-0.96(m, 2H). 76 6-methyl-4-[4-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s,365.2 pyridyl)ethyl]piperidine- 1H), 8.49-8.39 (m, 2H), 7.40 (s, 1H),1-carbonyl]-1H- 7.33 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H),pyrrolo[2,3-c]pyridin-7- 6.25 (d, J = 2.9 Hz, 1H), 4.05 (s, 2H), 3.53(s, one 3H), 2.96-2.74 (m, 2H), 2.68-2.54 (m, 2H), 7.22-7.17 (m, 0H),1.73 (d, J = 12.5 Hz, 2H), 1.65-1.39 (m, 4H), 1.20-0.99 (m, 2H). 776-methyl-4-(4-pyrrolidin- ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 329.21-ylpiperidine-1- 1H), 7.41 (s, 1H), 7.33 (d, J = 2.8 Hz, 1H),carbonyl)-1H- 6.24 (d, J = 2.8 Hz, 1H), 3.93 (s, 2H), 3.53 (s,pyrrolo[2,3-c]pyridin-7- 3H), 3.08-2.96 (m, 2H), 2.48-2.44 (m, 4H), one2.26-2.15 (m, 1H), 1.86-1.78 (m, 2H), 1.72-1.62 (m, 4H), 1.43-1.28 (m,2H). 78 4-[4-(dimethylamino)-3- ¹H NMR (400 MHz, DMSO-d6) δ 7.38 (s,317.2 methyl-piperidine-1- 1H), 7.32 (d, J = 2.7 Hz, 1H), 6.21 (d, J =2.7 Hz, carbonyl]-6-methyl-1H- 1H), 3.53 (s, 3H), 2.86 (d, J = 17.9 Hz,pyrrolo[2,3-c]pyridin-7- 2H), 2.15 (m, 2H), 2.12 (s, 6H), 1.95 (dt, J =11.5, one 4.0 Hz, 1H), 1.69 (d, J = 12.7 Hz, 1H), 1.33 (dt, J = 12.5,6.3 Hz, 1H), 0.80 (dd, J = 22.1, 6.9 Hz, 4H). 79 4-[4- ¹H NMR (400 MHz,DMSO-d6) δ 12.19 (s, 331.2 (diethylamino)piperidine- 1H), 7.44 (s, 1H),7.35 (t, J = 2.8 Hz, 1H), 1-carbonyl]-6-methyl- 6.29 (t, J = 2.4 Hz,1H), 4.16 (m, 2H), 3.54 (s, 1H-pyrrolo[2,3- 3H), 3.11-2.80 (m, 6H), 1.93(s, 2H), 1.55 (s, c]pyridin-7-one 2H), 1.18 (t, J = 7.1 Hz, 6H). 806-methyl-N-(m-tolyl)-7- 1H NMR (400 MHz, DMSO-d6) d 282oxo-1H-pyrrolo[2,3- 12.07-12.21 (m, 1H), 9.84 (s, 1H), 8.03 (s, 1H),c]pyridine-4- 7.57 (s, 1H), 7.48-7.53 (m, 1H), 7.35 (t, J = 2.70 Hz,carboxamide 1H), 7.22 (s, 1H), 6.86-6.92 (m, 1H), 6.72 (t, J = 2.39 Hz,1H), 3.60 (s, 3H), 2.31 (s, 3H). 81 N-cyclopropyl-6-methyl- ¹H NMR (400MHz, DMSO-d₆) δ 12.05 (s, 328 N-(1-methyl-4- 1H), 7.93 (d, J = 4.2 Hz,1H), 7.76 (s, 1H), piperidyl)-7-oxo-1H- 7.33-7.27 (m, 1H), 6.72-6.66 (m,1H), pyrrolo[2,3-c]pyridine-4- 3.53 (s, 3H), 3.06 (d, J = 8.7 Hz, 2H),2.95 (d, J = 3.8 Hz, carboxamide 1H), 2.42-2.32 (m, 3H), 1.57 (s, 2H),0.98 (d, J = 6.2 Hz, 6H). 82 N-cyclopropyl-6-methyl- ¹H NMR (400 MHz,DMSO-d₆) δ 12.03 (s, 356 7-oxo-N-(1-propyl-4- 1H), 7.45 (s, 1H), 7.28(d, J = 2.8 Hz, 1H), piperidyl)-1H- 6.25 (d, J = 2.7 Hz, 1H), 3.89 (tt,J = 12.1, 3.9 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.53 (s, 3H), 3.30 (d,J = 16.5 Hz, carboxamide 2H), 2.96-2.89 (m, 2H), 2.72-2.61 (m, 1H),2.26-2.17 (m, 2H), 2.10-1.95 (m, 2H), 1.94-1.83 (m, 2H), 1.82-1.74 (m,2H), 1.50-1.36 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H), 0.61-0.51 (m, 2H),0.47-0.38 (m, 2H).

Example 83N-(cyclopentylmethyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a 1 dram vial was added cyclopentylmethanamine hydrochloride (34 mg,0.25 mmol) followed by6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylicacid (Intermediate E) (Step 1, 0.5 mL, 0.25 mmol, 0.5 M in DMF), HATU(0.76 mL, 0.38 mmol, 0.5 M in DMF) and triethylamine (3 equiv., 0.75mmol). The reaction was shaken at room temperature overnight. The DMFwas removed under reduced pressure, and then methanol (1.5 mL) andpotassium hydroxide (1 mL, 1.0 mmol, IM in water) were added. Thereaction was heated at 60° C. overnight. After cooling the reaction waspartitioned between dichloromethane and water. The organic solution wasseparated and concentrated under reduced pressure. The residue waspurified by reverse phase chromatography (5-85% ACN/0.1% NH4OH in H2O)yieldingN-(cyclopentylmethyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide.(7.5 mg, 11%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.93 (t, J=5.8Hz, 1H), 7.79 (s, 1H), 7.31 (t, J=2.4 Hz, 1H), 6.72-6.66 (m, 1H), 3.55(s, 3H), 3.23-3.07 (m, 2H), 2.14 (p, J=7.4 Hz, 1H), 1.76-1.65 (m, 2H),1.65-1.44 (m, 4H), 1.33-1.19 (m, 2H). LCMS M/Z (M+H) 274.

The following compounds were prepared in a similar manner to Example 83:Examples 84-138

Example Compound Name NMR m/z 84 N-(2-methoxyethyl)-6- ¹H NMR (400 MHz,DMSO-d₆) δ 12.14 (s, 346 methyl-N-(1-methyl-4- 1H), 7.37-7.24 (m, 2H),6.17 (dd, J = 2.7, 1.9 Hz, piperidyl)-7-oxo-1H 1H), 3.71 (d, J = 12.1Hz, 1H), 3.52 (s, pyrrolo[2,3-c]pyridine-4- 3H), 3.49-3.36 (m, 2H), 3.23(s, 2H), carboxamide 2.95-2.77 (m, 2H), 2.18 (s, 2H), 1.98-1.80 (m, 4H),1.71-1.56 (m, 2H). 85 6-methyl-4-(2- ¹H NMR (400 MHz, DMSO-d6) δ 12.07(br. 322 phenylpyrrolidine-1- s., 1H), 7.48-7.85 (m, 1H), 7.09-7.44 (m,carbonyl)-1H- 6H), 6.34 (br. s., 1H), 5.27-6.10 (m, 3H),pyrrolo[2,3-c]pyridin-7- 5.14 (br. s., 1H), 3.82 (br. s., 1H), 3.38-3.73(m, one 2H), 2.37 (dd, J = 6.23, 12.46 Hz, 1H), 1.66-1.97 (m, 2H). 86N-(cyclohexylmethyl)-6- ¹H NMR (400 MHz, DMSO-d6) d 11.96 (bs, 288methyl-7-oxo-1H- 1H), 7.81 (t, J = 5.49 Hz, 1H), 7.71 (s, 1H),pyrrolo[2,3-c]pyridine-4- 7.19-7.23 (m, 1H), 6.59 (d, J = 2.44 Hz, 1H),carboxamide 3.50-4.00 (bs, 3H), 2.98 (t, J = 6.35 Hz, 2H), 1.34-1.72 (m,6H), 0.98-1.15 (m, 3H), 0.70-0.90 (m, 2H). 87 N-benzyl-N,6-dimethyl- ¹HNMR (400 MHz, DMSO-d6) d 12.05 (br. 296 7-oxo-1H-pyrrolo[2,3- s., 1H),7.39 (s, 1H), 7.05-7.33 (m, 6H), c]pyridine-4- 6.14 (bs, 1H), 4.54 (s,2H), 3.27-3.50 (m, 3H), carboxamide 2.65-2.86 (m, 3H). 886-methyl-4-(1,2,3,5- ¹H NMR (400 MHz, DMSO-d6) δ 12.14 (br. 323tetrahydro-1,4- s., 1H), 7.28-7.34 (m, 1H), 7.14-7.27 (m,benzodiazepine-4- 1H), 7.06 (t, J = 7.48 Hz, 1H), 6.85 (d, J = 7.89 Hz,carbonyl)-1H- 1H), 6.74 (br. s., 1H), 6.20-6.24 (m, 1H),pyrrolo[2,3-c]pyridin-7- 4.56 (br. s., 2H), 3.70 (br. s., 1H), 3.45 (s,3H), one 3.15 (br. s., 2H). 89 6-methyl-4-(3- ¹H NMR (400 MHz, DMSO-d6)d = 12.09 (br. 322 phenylpyrrolidine-1- s., 1 H), 7.55 (s, 1 H),7.39-7.26 (m, 5 H), carbonyl)-1H- 7.26-7.18 (m, 1 H), 6.38 (t, J = 2.4Hz, 1 H), pyrrolo[2,3-c]pyridin-7- 3.88 (br. s, 1 H), 3.73-3.31 (m, 7H), 2.26 (br. one s., 1 H), 2.07 (s, 1 H). 90 N-[(1S)-2-amino-2-oxo- ¹HNMR (400 MHz, DMSO-d6) δ 325 1-phenyl-ethyl]-6- 12.00-12.38 (m, 1H),8.16-8.25 (m, 1H), 8.04 (s, methyl-7-oxo-1H- 1H), 7.72-7.81 (m, 1H),7.47-7.56 (m, 2H), pyrrolo[2,3-c]pyridine-4- 7.36 (s, 5H), 6.67-6.72 (m,1H), carboxamide 5.56-5.63 (m, 1H), 3.56 (s, 3H). 91N-benzhydryl-6-methyl- ¹H NMR (400 MHz, DMSO-d6) δ 3587-oxo-1H-pyrrolo[2,3- 11.95-12.18 (m, 1H), 8.69-8.87 (m, 1H), 8.05 (s,c]pyridine-4- 1H), 7.32-7.41 (m, 7H), 7.30 (s, 3H), carboxamide6.64-6.73 (m, 1H), 6.33-6.41 (m, 1H), 3.56 (s, 3H). 92 6-methyl-N-[(4-¹H NMR (400 MHz, DMSO-d6) d = 12.12 (br. 360methylsulfonylphenyl)methyl]- s., 1 H), 8.65 (t, J = 5.9 Hz, 1 H), 7.94(s, 1 H), 7-oxo-1H- 7.92-7.85 (m, 2 H), 7.60 (d, J = 8.5 Hz, 2 H),pyrrolo[2,3-c]pyridine-4- 7.33 (t, J = 2.8 Hz, 1 H), 6.80-6.69 (m, 1 H),carboxamide 4.56 (d, J = 5.8 Hz, 2 H), 3.56 (s, 3 H), 3.19 (s, 3H). 93methyl (2S)-2- ¹H NMR (400 MHz, DMSO-d6) δ 12.09 (br. 346cyclohexyl-2-[(6-methyl- s., 1H), 8.08 (d, J = 7.69 Hz, 1H), 7.97 (s,1H), 7-oxo-1H-pyrrolo[2,3- 7.32 (t, J = 2.80 Hz, 1H), 6.68 (t, J = 2.39Hz, c]pyridine-4- 1H), 4.33 (t, J = 7.69 Hz, 1H), 3.65 (s, 3H),carbonyl)amino]acetate 3.57 (s, 3H), 1.56-1.88 (m, 4H), 1.00-1.30 (m,6H). 94 N-[(1R)-1- . ¹H NMR (400 MHz, DMSO-d6) δ 12.05 (br. 302cyclohexylethyl]-6- s., 1H), 7.81 (s, 1H), 7.63 (d, J = 8.52 Hz, 1H),methyl-7-oxo-1H- 7.30 (t, J = 2.70 Hz, 1H), 6.68 (t, J = 2.39 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 3.77-3.91 (m, 1H), 3.53-3.58 (m, 3H),carboxamide 1.66-1.81 (m, 4H), 1.61 (d, J = 9.14 Hz, 1H), 1.39 (dd, J =3.43, 7.17 Hz, 1H), 1.12-1.26 (m, 2H), 1.09 (d, J = 6.65 Hz, 3H),0.89-1.04 (m, 2H). 95 N-[(1S)-2-methoxy-1- ¹H NMR (400 MHz, DMSO-d6) δ12.09 (br. 326 phenyl-ethyl]-6-methyl- s., 1H), 8.33 (d, J = 8.10 Hz,1H), 7.94 (s, 1H), 7-oxo-1H-pyrrolo[2,3- 7.39-7.46 (m, 2H), 7.29-7.38(m, 3H), c]pyridine-4- 7.21-7.28 (m, 1H), 6.68 (t, J = 2.39 Hz, 1H),carboxamide 5.21-5.30 (m, 1H), 3.64-3.71 (m, 1H), 3.58 (s, 3H),3.53-3.57 (m, 2H), 3.30 (s, 3H). 96 (2S)-2-[(6-methyl-7-oxo- ¹H NMR (400MHz, DMSO-d6) δ 12.94 (br. 326 1H-pyrrolo[2,3- s., 1H), 12.10 (br. s.,1H), 8.48 (d, J = 7.27 Hz, c]pyridine-4- 1H), 8.04 (s, 1H), 7.50 (d, J =7.27 Hz, 2H), carbonyl)amino]-2- 7.31-7.43 (m, 3H), 6.73 (s, 1H), 5.56(d, J = 7.06 Hz, phenyl-acetic acid 1H), 3.34 (br. s., 3H). 97N-[(1R)-2-amino-2-oxo- ¹H NMR (400 MHz, DMSO-d6) δ 12.15 (br. 3251-phenyl-ethyl]-6- s., 1H), 8.21 (d, J = 7.48 Hz, 1H), 8.04 (s, 1H),methyl-7-oxo-1H- 7.76 (s, 1H), 7.51 (d, J = 7.27 Hz, 2H),pyrrolo[2,3-c]pyridine-4- 7.34-7.39 (m, 3H), 7.26-7.32 (m, 2H), 6.70 (t,J = 2.39 Hz, carboxamide 1H), 5.60 (d, J = 7.69 Hz, 1H), 3.56 (s, 3H).98 N-[(1S)-1-carbamoyl-2- ¹H NMR (400 MHz, DMSO-d6) δ 12.14 (br. 291methyl-propyl]-6-methyl- s., 1H), 7.96 (s, 1H), 7.57 (d, J = 8.72 Hz,1H), 7-oxo-1H-pyrrolo[2,3- 7.52 (s, 1H), 7.35 (t, J = 2.80 Hz, 1H), 7.13(s, c]pyridine-4- 1H), 6.68 (t, J = 2.29 Hz, 1H), 4.35 (dd, J = 6.65,carboxamide 8.72 Hz, 1H), 3.55-3.60 (m, 3H), 2.03-2.14 (m, 1H), 0.93 (t,J = 6.54 Hz, 6H). 99 1-(6-methyl-7-oxo-1H- ¹H NMR (400 MHz, DMSO-d6) δ12.06 (br. 289 pyrrolo[2,3-c]pyridine-4- s., 1H), 7.57 (br. s., 1H),7.24-7.40 (m, 2H), carbonyl)pyrrolidine-2- 6.94 (br. s., 1H), 6.39 (br.s., 1H), 4.41 (br. s., carboxamide 1H), 3.60 (br. s., 2H), 2.11-2.25 (m,1H), 1.68-1.94 (m, 3H). 100 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6)δ 12.06 (br. 290 (tetrahydropyran-3- s., 1H), 7.96 (t, J = 5.82 Hz, 1H),7.81 (s, 1H), ylmethyl)-1H- 7.31 (t, J = 2.80 Hz, 1H), 6.58-6.74 (m,1H), pyrrolo[2,3-c]pyridine-4- 3.76-3.84 (m, 1H),3.71 (td, J = 3.61,11.06 Hz, carboxamide 1H), 3.54 (s, 3H), 3.31 (dt, J = 2.80, 10.75 Hz,1H), 3.00-3.19 (m, 3H), 1.71-1.87 (m, 2H), 1.53-1.64 (m, 1H), 1.45 (m,1H), 1.13-1.32 (m, 1H). 101 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6)d 12.06 (bs, 290 (tetrahydropyran-4- 1H), 7.98 (t, J = 5.77 Hz, 1H),7.82 (s, 1H), ylmethyl)-1H- 7.30 (t, J = 2.61 Hz, 1H), 6.68 (t, J = 2.47Hz, pyrrolo[2,3-c]pyridine-4- 1H), 3.60-3.97 (m, 5H), 3.26 (dt, J =1.79, carboxamide 11.60 Hz, 2H), 3.13 (t, J = 6.32 Hz, 2H), 1.76 (dt, J= 4.12, 7.55 Hz, 1H), 1.60 (d, J = 12.91 Hz, 2H), 1.05-1.32 (m, 3H). 1026-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6) d 12.07 (br. 276(tetrahydrofuran-3- s., 1H), 8.06 (t, J = 5.91 Hz, 1H), 7.80 (s, 1H),ylmethyl)-1H- 7.31 (t, J = 2.75 Hz, 1H), 6.68 (t, J = 2.47 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 3.57-3.80 (m, 2H), 3.54 (s, 2H),carboxamide 3.47 (dd, J = 5.22, 8.51 Hz, 1H), 3.10-3.27 (m, 1H), 1.94(dd, J = 5.63, 12.22 Hz, 1H), 1.45-1.70 (m, 1H). 103N-(cycloheptylmethyl)-6- ¹H NMR (400 MHz, DMSO-d6) d 12.06 (bs, 302methyl-7-oxo-1H- 1H), 7.93 (t, J = 5.77 Hz, 1H), 7.81 (s, 1H),pyrrolo[2,3-c]pyridine-4- 7.31 (t, J = 2.75 Hz, 1H), 6.68 (t, J = 2.33Hz, carboxamide 1H), 3.07 (t, J = 6.04 Hz, 2H), 1.26-1.75 (m, 11H),1.04-1.25 (m, 2H). 104 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6) d12.05 (bs, 262 tetrahydrofuran-3-yl-1H- 1H), 8.09 (d, J = 6.32 Hz, 1H),7.86 (s, 1H), pyrrolo[2,3-c]pyridine-4- 7.30 (t, J = 2.61 Hz, 1H), 6.69(s, 1H), 4.43 (d, carboxamide J = 5.77 Hz, 1H), 3.78-3.92 (m, 2H),3.65-3.78 (m, 2H), 2.14 (dd, J = 7.14, 12.63 Hz, 1H), 1.71-1.97 (m, 1H).105 N-[(1,1-dioxothiolan-3- ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (br. 324yl)methyl]-6-methyl-7- s., 1H), 8.16 (t, J = 5.71 Hz, 1H), 7.84 (s, 1H),oxo-1H-pyrrolo[2,3- 7.33 (t, J = 2.80 Hz, 1H), 6.70 (t, J = 2.18 Hz,c]pyridine-4- 1H), 3.54-3.58 (m, 3H), 3.30-3.44 (m, 2H), carboxamide3.16-3.30 (m, 2H), 3.02-3.13 (m, 1H), 2.87 (dd, J = 9.56, 13.09 Hz, 1H),2.60-2.73 (m, 1H), 2.24 (d, J = 4.78 Hz, 1H), 1.79-1.92 (m, 1H). 1066-methyl-N-(1- ¹H NMR (400 MHz, DMSO-d6) δ 12.05 (br. 314norbornan-2-ylethyl)-7- s., 1H), 7.75-7.82 (m, 1H), 7.57-7.74 (m,oxo-1H-pyrrolo[2,3- 1H), 7.23-7.36 (m, H), 6.59-6.75 (m, 1H),c]pyridine-4- 3.60-3.92 (m, 2H), 3.52-3.58 (m, 3H), carboxamide2.10-2.30 (m, 2H), 1.91 (br. s., 1H), 1.72 t, J = 11.84 Hz, 1H),0.99-1.61 (m, 11H), 0.65-0.85 (m, 1H). 107 N-[(1R,2S)-2-hydroxy- ¹H NMR(400 MHz, DMSO-d6) δ 388 1,2-diphenyl-ethyl]-6- 11.99-12.13 (m, 1H),8.09-8.21 (m, 1H), 7.63 (s, methyl-7-oxo-1H- 1H), 7.33-7.42 (m, 4H),7.15-7.32 (m, 7H), pyrrolo[2,3-c]pyridine-4- 6.44 (s, 1H), 5.49-5.57 (m,1H), carboxamide 5.11-5.21 (m, 1H), 4.87-4.97 (m, 1H), 3.53 (s, 3H). 108N-(chroman-3-ylmethyl)- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 3386-methyl-7-oxo-1H- 1H), 8.13 (t, J = 5.8 Hz, 1H), 7.86 (s, 1H),pyrrolo[2,3-c]pyridine-4- 7.32 (t, J = 2.7 Hz, 1H), 7.11-7.03 (m, 2H),carboxamide 6.86-6.79 (m, 1H), 6.78-6.69 (m, 2H), 4.28-4.20 (m, 1H),3.92-3.84 (m, 1H), 3.56 (s, 2H), 3.30 (s, 3H), 2.91-2.81 (m, 1H),2.71-2.53 (m, 1H), 2.28 (s, 1H). 109 tert-butyl 3-[(6-methyl-7- ¹H NMR(400 MHz, DMSO-d₆) δ 12.05 (s, 361 oxo-1H-pyrrolo[2,3- 1H), 8.08 (d, J =6.6 Hz, 1H), 7.85 (s, 1H), c]pyridine-4- 7.31 (t, J = 2.5 Hz, 1H),6.74-6.62 (m, 1H), carbonyl)amino]pyrrolidine- 4.39 (s, 1H), 3.55 (s,4H), 3.51-3.35 (m, 1H), 1-carboxylate 3.28-3.26 (m, 1H), 3.18 (s, 1H),2.10 (s, 1H), 1.98-1.73 (m, 1H), 1.41 (s, 9H). 110 N-(2,3- ¹H NMR (400MHz, DMSO-d₆) δ 12.06 (s, 324 dihydrobenzofuran-2- 1H), 8.17 (t, J = 5.8Hz, 1H), 7.77 (s, 1H), ylmethyl)-6-methyl-7- 7.31 (t, J = 2.6 Hz, 1H),7.23-7.16 (m, 1H), oxo-1H-pyrrolo[2,3- 7.14-7.04 (m, 1H), 6.86-6.72 (m,2H), c]pyridine-4- 6.72-6.63 (m, 1H), 5.01-4.91 (m, 1H), 3.53 (s, 5H),carboxamide 3.29-3.26 (m, 1H), 3.08-2.95 (m, 1H). 111N-(2,3-dihydro-1,4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.08 (s, 340benzodioxin-3-ylmethyl)- 1H), 8.23 (t, J = 5.8 Hz, 1H), 7.89 (s, 1H),6-methyl-7-oxo-1H- 7.34-7.26 (m, 1H), 6.92-6.80 (m, 4H), 6.73 (d, J =2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 4.41-4.29 (m, 2H), carboxamide4.05-3.97 (m, 1H), 3.65-3.45 (m, 5H). 112 N-(1-cyclopropylethyl)- ¹H NMR(400 MHz, DMSO-d₆) δ 12.03 (s, 260 6-methyl-7-oxo-1H- 1H), 7.80 (d, J =9.9 Hz, 2H), 7.30 (d, J = 2.7 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 6.69(d, J = 2.7 Hz, 1H), 3.56 (s, 3H), carboxamide 3.53-3.43 (m, 1H), 1.21(d, J = 6.7 Hz, 3H), 1.05-0.85 (m, 1H), 0.51-0.26 (m, 3H), 0.26-0.14 (m,1H). 113 6-methyl-N-[3- ¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 367(morpholinomethyl)phenyl]- 8.31 (s, 2H), 8.06 (s, 1H), 7.73-7.62 (m,2H), 7-oxo-1H- 7.34 (d, J = 2.7 Hz, 1H), 7.31-7.24 (m, 1H),pyrrolo[2,3-c]pyridine-4- 7.04-6.98 (m, 1H), 6.73 (d, J = 2.7 Hz, 1H),carboxamide 3.60 (s, 3H), 3.58 (s, 3H), 3.45 (s, 2H), 2.43-2.30 (m, 4H).114 6-methyl-N-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 332naphthylmethyl)-7-oxo- 1H), 8.50 (s, 1H), 8.26-8.14 (m, 1H),1H-pyrrolo[2,3- 8.02-7.82 (m, 3H), 7.61-7.45 (m, 4H), 7.32 (t, J = 2.7Hz, c]pyridine-4- 1H), 6.77-6.72 (m, 1H), 4.94 (d, J = 5.6 Hz,carboxamide 2H), 3.53 (s, 3H). 115 6-methyl-7-oxo-N-[1-(4- ¹H NMR (400MHz, DMSO-d₆) δ 12.06 (s, 297 pyridyl)ethyl]-1H- 1H), 8.54-8.48 (m, 2H),8.43 (d, J = 7.5 Hz, pyrrolo[2,3-c]pyridine-4- 1H), 7.97 (s, 1H),7.41-7.37 (m, 2H), 7.30 (d, carboxamide J = 2.7 Hz, 1H), 6.67 (d, J =2.7 Hz, 1H), 5.10 (t, J = 7.2 Hz, 1H), 3.58 (s, 3H), 1.47 (d, J = 7.1Hz, 3H). 116 N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 314fluorophenyl)ethyl]-6- 1H), 8.38 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H),methyl-7-oxo-1H- 7.56-7.45 (m, 1H), 7.33-7.24 (m, 2H),pyrrolo[2,3-c]pyridine-4- 7.22-7.10 (m, 2H), 6.68-6.64 (m, 1H), 537 (p,J = 7.1 Hz, carboxamide 1H), 3.58 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H). 117N-(2-ethoxypropyl)-6- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 278methyl-7-oxo-1H- 1H), 7.84 (d, J = 9.9 Hz, 2H), 7.33 (d, J = 2.7 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 6.69 (d, J = 2.7 Hz, 1H), carboxamide3.63-3.40 (m, 6H), 3.28-3.21 (m, 2H), 1.11 (t, J = 6.8 Hz, 6H). 118N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 331chlorophenyl)ethyl]-6- 1H), 8.46 (d, J = 7.4 Hz, 1H), 8.00 (s, 1H),methyl-7-oxo-1H- 7.61-7.52 (m, 1H), 7.47-7.38 (m, 1H),pyrrolo[2,3-c]pyridine-4- 7.37-7.21 (m, 3H), 6.68-6.64 (m, 1H), 5.42 (t,J = 7.1 Hz, carboxamide 1H), 3.59 (s, 3H), 1.44 (d, J = 7.0 Hz, 3H). 119N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 326methoxyphenyl)ethyl]-6- 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H),methyl-7-oxo-1H- 7.40-7.33 (m, 1H), 7.30 (t, J = 2.4 Hz, 1H),pyrrolo[2,3-c]pyridine-4- 7.27-7.17 (m, 1H), 7.03-6.95 (m, 1H),carboxamide 6.95-6.87 (m, 1H), 6.66-6.63 (m, 1H), 5.47-5.35 (m, 1H),3.85 (s, 3H), 3.58 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H). 120N-[1-(2,3-dihydro-1,4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 354benzodioxin-6-yl)ethyl]- 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.90 (s, 1H),6-methyl-7-oxo-1H- 7.29 (t, J = 2.2 Hz, 1H), 6.89 (d, J = 2.1 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 6.86-6.82 (m, 1H), 6.78 (d, J = 8.3 Hz,carboxamide 1H), 6.69-6.66 (m, 1H), 5.03 (t, J = 7.3 Hz, 1H), 4.23-4.17(m, 4H), 3.56 (s, 3H), 1.41 (d, J = 7.0 Hz, 3H). 121N-isochroman-4-yl-6- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 324methyl-7-oxo-1H- 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H),pyrrolo[2,3-c]pyridine-4- 7.37-7.30 (m, 2H), 7.29-7.21 (m, 2H),carboxamide 7.15-7.09 (m, 1H), 6.77 (d, J = 2.7 Hz, 1H), 5.29-5.13 (m,1H), 4.83-4.67 (m, 2H), 4.04-3.91 (m, 1H), 3.86-3.75 (m, 1H), 3.52 (s,3H). 122 6-methyl-N-[1-methyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s,315 (3-methylisoxazol-5- 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H),yl)ethyl]-7-oxo-1H- 7.31 (d, J = 2.8 Hz, 1H), 6.66 (d, J = 2.7 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 6.14 (s, 1H), 4.37-4.23 (m, 1H), 3.55 (s,carboxamide 3H), 3.07-2.85 (m, 2H), 2.17 (s, 3H), 1.19 (d, J = 6.6 Hz,3H). 123 6-methyl-N-(2-methyl-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s,324 phenyl-propyl)-7-oxo- 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H),1H-pyrrolo[2,3- 7.45-7.12 (m, 6H), 6.62 (m, J = 2.9, 1.3 Hz,c]pyridine-4- 1H), 4.70 (t, J = 8.9 Hz, 1H), 3.57 (s, 3H), carboxamide2.10 (m, J = 9.1, 6.6 Hz, 1H), 1.02 (d, J = 6.6 Hz, 3H), 0.74 (d, J =6.7 Hz, 3H). 124 N-[4-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 356fluorophenyl)tetrahydrofuran- 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.41 (s,1H), 3-yl]-6-methyl-7- 7.32-7.26 (m, 2H), 7.22 (t, J = 2.4 Hz, 1H),oxo-1H-pyrrolo[2,3- 7.07 (t, J = 8.9 Hz, 2H), 6.33-6.30 (m, 1H),c]pyridine-4- 4.92-4.81 (m, 1H), 4.18-4.10 (m, 2H), carboxamide4.07-3.99 (m, 1H), 3.82-3.74 (m, 1H), 3.73-3.64 (m, 1H), 3.47 (s, 3H).125 6-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 322tetralin-1-yl-1H- 1H), 8.24 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H),pyrrolo[2,3-c]pyridine-4- 7.32 (t, J = 2.6 Hz, 1H), 7.27-7.21 (m, 1H),carboxamide 7.19-7.08 (m, 3H), 6.79-6.75 (m, 1H), 5.31-5.15 (m, 1H),3.52 (s, 3H), 3.28-3.26 (m, 1H), 2.86-2.69 (m, 2H), 2.05-1.91 (m, 2H),1.87-1.71 (m, 1H). 126 N-[1-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s,331 chlorophenyl)ethyl]-6- 1H), 8.34 (d, J = 7.7 Hz, 1H), 7.93 (s, 1H),methyl-7-oxo-1H- 7.48-7.33 (m, 3H), 7.29 (t, J = 2.7 Hz, 1H),pyrrolo[2,3-c]pyridine-4- 6.67 (d, J = 2.0 Hz, 1H), 5.12 (t, J = 7.2 Hz,carboxamide 1H), 3.57 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H). 1276-methyl-N-[2-(o- ¹H NMR (400 MHz, DMSO-d₆) δ 310 tolyl)ethyl]-7-oxo-1H-12.32-12.04 (m, 1H), 7.48 (s, 1H), 7.32 (d, J = 2.8 Hz,pyrrolo[2,3-c]pyridine-4- 1H), 7.26-7.05 (m, 4H), 6.24 (d, J = 2.8 Hz,carboxamide 1H), 4.70 (s, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.54 (s, 3H),3.27 (d, J = 0.9 Hz, 1H), 2.94-2.73 (m, 3H). 128 N,6-dimethyl-7-oxo-N-¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 310 (1-phenylethyl)-1H- 1H),7.64-7.07 (m, 8H), 5.62 (d, J = 16.2 Hz, pyrrolo[2,3-c]pyridine-4- 1H),3.53 (s, 3H), 3.27 (s, 1H), 2.63 (s, 3H), carboxamide 1.57 (d, J = 7.0Hz, 3H). 129 N-[1-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 314fluorophenyl)ethyl]-6- 1H), 8.31 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H),methyl-7-oxo-1H- 7.46-7.39 (m, 2H), 7.29 (t, J = 2.5 Hz, 1H),pyrrolo[2,3-c]pyridine-4- 7.18-7.10 (m, 2H), 6.69-6.65 (m, 1H),carboxamide 5.14 (t, J = 7.3 Hz, 1H), 3.57 (s, 3H), 1.46 (d, J = 7.1 Hz,3H). 130 tert-butyl 3-[[(6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s,361 7-oxo-1H-pyrrolo[2,3- 1H), 8.10 (t, J = 5.8 Hz, 1H), 7.32 (t, J =2.5 Hz, c]pyridine-4- 1H), 6.73-6.63 (m, 1H), 3.87 (d, J = 8.8 Hz,carbonyl)amino]methyl]azetidine- 2H), 3.55 (s, 5H), 3.47-3.39 (m, 2H),1-carboxylate 3.27 (t, J = 0.8 Hz, 1H), 2.82-2.63 (m, 1H), 1.36 (s, 9H).131 6-methyl-N-(1-methyl-1- ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 310phenyl-ethyl)-7-oxo-1H- 1H), 7.95 (d, J = 15.2 Hz, 2H), 7.45-7.35 (m,pyrrolo[2,3-c]pyridine-4- 2H), 7.33-7.24 (m, 3H), 7.21-7.12 (m, 1H),carboxamide 6.63-6.55 (m, 1H), 3.58 (s, 3H), 1.67 (s, 6H). 132tert-butyl 2-[[6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 3907-oxo-1H-pyrrolo[2,3- 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.31 (t, J = 2.5Hz, c]pyridine-4- 1H), 6.76-6.66 (m, 1H), 4.35 (d, J = 7.0 Hz,carbonyl)amino]methyl]piperidine- 1H), 3.86 (d, J = 13.3 Hz, 1H), 3.54(s, 1-carboxylate 3H), 3.36 (m, J = 13.1, 6.3 Hz, 1H), 3.27 (s, 1H),2.93 (s, 1H), 1.71-1.34 (m, 5H), 1.28 (s, 10H). 133 tert-butyl4-[[(6-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 3907-oxo-1H-pyrrolo[2,3- 1H), 7.97 (t, J = 5.8 Hz, 1H), 7.81 (s, 1H),c]pyridine-4- 7.31 (t, J = 2.7 Hz, 1H), 6.78-6.62 (m, 1H),carbonyl)amino]methyl]piperidine- 4.08-3.81 (m, 2H), 3.55 (s, 3H), 3.14(t, J = 6.1 Hz, 1-carboxylate 2H), 2.85-2.60 (m, 2H), 1.84-1.57 (m, 3H),1.39 (s, 9H), 1.18-0.89 (m, 2H). 134 tert-butyl 2-[[(6-methyl- ¹ H NMR(400 MHz, DMSO-d₆) δ 12.08 (s, 391 7-oxo-1H-pyrrolo[2,3- 1H), 8.03 (t, J= 5.8 Hz, 1H), 7.85 (s, 1H), c]pyridine-4- 7.32 (d, J = 2.8 Hz, 1H),6.71 (d, J = 2.7 Hz, 1H), carbonyl)amino]methyl] 3.92-3.77 (m, 2H), 3.70(d, J = 13.4 Hz, 1H), morpholine-4- 3.52-3.43 (m, 1H), 3.43-3.35 (m,1H), carboxylate 3.33 (d, J = 6.0 Hz, 5H), 2.89 (s, 1H), 2.71-2.55 (m,1H), 1.39 (s, 9H). 135 tert-butyl 3-[[(6-methyl- ¹H NMR (400 MHz,DMSO-d₆) δ 12.06 (s, 390 7-oxo-1H-pyrrolo[2,3- 1H), 7.98 (t, J = 5.8 Hz,1H), 7.81 (s, 1H), c]pyridine-4- 7.32 (t, J = 2.7 Hz, 1H), 6.71 (d, J =2.7 Hz, 1H), carbonyl)amino]methyl]piperidine- 3.89 (s, 1H), 3.76 (d, J= 13.2 Hz, 1H), 3.55 (s, 1-carboxylate 3H), 3.27 (s, 2H), 3.17-3.08 (m,2H), 2.84-2.72 (m, 1H), 1.77 (d, J = 12.5 Hz, 1H), 1.71-1.56 (m, 2H),1.36 (s, 10H), 1.22-1.12 (m, 1H). 136 tert-butyl 2-[[(6-methyl- ¹H NMR(400 MHz, DMSO-d₆) δ 12.05 (s, 275 7-oxo-1H-pyrrolo[2,3- 1H), 7.98 (s,1H), 7.82 (s, 1H), 7.31 (t, J = 2.4 Hz, c]pyridine-4- 1H), 6.71 (s, 1H),3.90 (s, 1H), 3.55 (s, carbonyl)amino]methyl]pyrrolidine- 3H), 1.41 (s,9H). 1-carboxylate 137 tert-butyl 3-[[(6-methyl- ¹H NMR (400 MHz,DMSO-d₆) δ 12.06 (s, 375 7-oxo-1H-pyrrolo[2,3- 1H), 8.06 (t, J = 5.8 Hz,1H), 7.82 (s, 1H), c]pyridine-4- 7.32 (t, J = 2.4 Hz, 1H), 6.72-6.66 (m,1H), carbonyl)amino]methyl]pyrrolidine- 3.55 (s, 3H), 3.28-3.16 (m, 4H),3.05-2.92 (m, 1-carboxylate 1H), 2.42 (s, 1H), 1.91 (d, J = 5.5 Hz, 1H),1.58 (d, J = 28.8 Hz, 1H), 1.39 (s, 10H). 138 tert-butyl 3-[(6-methyl-7-¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 375 oxo-1H-pyrrolo[2,3- 1H), 7.82(s, 1H), 7.75 (d, J = 7.5 Hz, 1H), c]pyridine-4- 7.31 (t, J = 2.3 Hz,1H), 6.70-6.65 (m, 1H), carbonyl)amino]piperidine- 4.05-3.59 (m, 3H),3.55 (s, 3H), 3.27 (t, J = 0.7 Hz, 1-carboxylate 2H), 2.85 (t, J = 11.6Hz, 1H), 1.90 (d, J = 8.4 Hz, 1H), 1.71 (s, 1H), 1.39 (s, 10H).

Example 139N,6-dimethyl-7-oxo-N-(1-pyrimidin-4-yl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: tert-butyl methyl(1-(pyrimidin-4-yl)piperidin-4-yl)carbamate

A mixture of tert-butyl methyl(piperidin-4-yl)carbamate (500 mg, 2.3mmol), cesium carbonate (836 mg, 2.6 mmol) and 4-chloropyrimidine (294mg, 2.6 mmol) in DMF (10 mL) was heated at 80° C. for 3 h, at which timeLCMS indicated full conversion of starting material. The reactionmixture was poured into ice water (10 mL) and extracted with ethylacetate (3×20 mL). The combined organic extracts were dried over sodiumsulfate and concentrated under reduced pressure to give the titlecompound (450 mg, 66.0% yield) as a yellow solid. This crude materialwas used in the next step without further purification.

Step 2: N-methyl-1-(pyrimidin-4-yl)piperidin-4-amine hydrochloride

To a cooled (0° C.) solution of tert-butylmethyl(1-(pyrimidin-4-yl)piperidin-4-yl)carbamate (300 mg, 1.0 mmol) inethyl acetate (50 mL) was added hydrogen chloride (2N in ethyl acetate,10 mL). After addition, the reaction mixture was stirred at 25° C. for 3h. The solvent was evaporated under reduced pressure to give the crudetitle compound (165 mg, 72% yield) as a yellow solid.

Step 3:N,6-dimethyl-7-oxo-N-(1-pyrimidin-4-yl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

A mixture of6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid(Intermediate C) (100 mg, 0.5 mmol), diisopropylethylamine (134 mg, 1.0mmol), HATU (150 mg, 0.6 mmol) and 1-(pyrimidin-4-yl)piperidin-4-aminehydrochloride (110 mg, 0.5 mmol) in DMF (5 mL) was stirred at 25° C. for3 h, at which time LCMS indicated the reaction had gone to completion.The reaction mixture was added to ice water (5 mL) and extracted withethyl acetate (3×10 mL). The combined organic extracts were dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by preparative HPLC, acetonitrile: water (10 nM ammonia):32%-62%, to give the title compound (11 mg, 5.8% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d6): δ 12.12 (s, 1H), 8.43 (d, J=9.6 Hz,1H), 8.12 (m, 1H), 7.38 (s, 1H), 7.30 (s, 1H), 6.83 (d, J=6.4 Hz, 1H),6.19 (d, J=2.4 Hz, 1H), 4.51-4.43 (m, 2H), 4.43-4.25 (m, 1H), 3.50 (s,3H), 2.91-2.81 (m, 2H), 2.75 (s, 3H), 1.76-1.63 (m, 4H). LCMS M/Z (M+H)367.2.

The following compounds were prepared in a similar fashion to Example139. Examples 140-158

Example Compound Name NMR m/z 140 N,6-dimethyl-N-[1-(5- ¹H NMR (400 MHz,DMSO-d6): δ 381 methylpyrimidin-2-yl)-4- 12.15 (br. s., 1 H), 8.21 (s, 2H), 7.41 (s, 1 H), piperidyl]-7-oxo-1H- 7.33 (s, 1 H), 6.22 (s, 1 H),4.72 (d, J = 12.4 Hz, pyrrolo[2,3-c]pyridine-4- 2 H), 4.39-4.31 (m, 1H), 3.53 (s, carboxamide 3 H), 2.79-2.74 (m, 5 H), 2.07 (s, 3 H),1.69-1.66 (m, 4 H) 141 N-[1-(5-cyanopyrimidin-2- ¹H NMR (400 MHz,DMSO-d6): δ 392 yl)-4-piperidyl]-N,6- 12.15 (br. s., 1 H), 8.75-8.72 (m,2 H), 7.41 (s, 1 dimethyl-7-oxo-1H- H), 7.33 (s, 1 H), 6.22 (d, J = 3.2Hz, 1 pyrrolo[2,3-c]pyridine-4- H), 4.85-4.81 (m, 2 H), 4.48-4.42 (m, 1carboxamide H), 3.53 (s, 3 H), 3.05-2.96 (m, 2 H), 2.79 (s, 3 H),1.78-1.72 (m, 4 H) 142 N,6-dimethyl-7-oxo-N-[1- ¹H NMR (400 MHz,DMSO-d6): δ 435 [4- 12.15 (br. s., 1 H), 8.67 (d, J = 4.4 Hz, 1 H),(trifluoromethyl)pyrimidin- 7.42 (s, 1 H), 7.33 (s, 1 H), 7.00 (d, J =5.2 Hz, 2-yl]-4-piperidyl]-1H- 1 H), 6.22 (s, 1 H), 4.79-4.75 (m,pyrrolo[2,3-c]pyridine-4- 2 H), 4.47-4.39 (m, 1 H), 3.53 (s, 3 H),carboxamide 2.99-2.92 (m., 2 H), 2.80 (s, 3 H), 1.77-1.70 (m, 4 H) 143N,6-dimethyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 367pyrazin-2-yl-4-piperidyl)- 12.13 (br. s., 1 H), 8.34 (s, 1 H), 8.06 (s,1 H), 1H-pyrrolo[2,3-c]pyridine- 7.80 (d, J = 2.4 Hz, 1 H), 7.41 (s, 1H), 4-carboxamide 7.38-7.31 (m, 1 H), 6.22 (s, 1 H), 4.47-4.34 (m, 3 H),3.53 (s, 3 H), 2.86-2.79 (m, 5 H), 1.78-1.71 (m, 4 H) 144N,6-dimethyl-N-[1-(4- ¹H NMR (400 MHz, CD₃OD): δ 8.14 (d, J = 5.2 Hz,381 methylpyrimidin-2-yl)-4- 1 H), 7.40-7.39 (m, 2 H),piperidyl]-7-oxo-1H- 6.47 (d, J = 5.2 H z, 1 H), 6.36 (d, J = 2.8 Hz, 1pyrrolo[2,3-c]pyridine-4- H), 4.88 (s, 3 H), 3.67 (s, 3 H), carboxamide2.93-2.75 (m, 5 H), 2.32 (s, 3 H), 1.87-1.81 (m, 4 H). 145N,6-dimethyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 367pyridazin-3-yl-4- 12.15 (br. s., 1 H), 8.52 (d, J = 3.6 Hz, 1 H),piperidyl)-1H-pyrrolo[2,3- 7.42-7.26 (m, 4 H), 6.23 (d, J = 2.4 Hz, 1c]pyridine-4-carboxamide H), 4.50 (d, J = 12.4 Hz, 2 H), 4.38-4.32 (m, 1H), 3.54 (s, 3 H), 2.91-2.85 (m, 2 H), 2.80 (s, 3 H), 1.83-1.75 (m, 4H). 146 N-[1-(4-cyanopyrimidin-2- ¹H NMR (400 MHz, DMSO-d6): δ 392yl)-4-piperidyl]-N,6- 12.10 (br. s., 1 H), 8.62 (d, J = 4.5 Hz, 1 H),dimethyl-7-oxo-1H- 7.40 (s, 1 H), 7.33 (s, 1 H), 7.11 (d, J = 4.5 Hz,pyrrolo[2,3-c]pyridine-4- 1 H), 6.22 (s, 1 H), 4.74-4.72 (m, carboxamide2 H), 4.38-4.30 (m, 1 H), 3.53 (s, 3 H), 2.96-2.86 (m, 2 H), 2.79-2.76(m, 3 H), 1.76-1.70 (m, 4 H) 147 N-[1-(5-fluoropyrimidin-2- ¹H NMR (400MHz, DMSO-d6): δ 385 yl)-4-piperidyl]-N,6- 12.15 (s, 1 H), 8.44 (s, 2H), 7.41 (s, 1 H), dimethyl-7-oxo-1H- 7.33 (s, 1 H), 6.22 (s, 1 H),4.70-4.65 (m, 2 H), pyrrolo[2,3-c]pyridine-4- 3.53 (s, 3 H), 3.31-3.28(m, 1 H), carboxamide 2.90-2.86 (m, 2 H), 2.79 (s, 3 H), 2.67 (s, 1 H),1.72-1.70 (m, 4 H). 148 6-methyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6):δ 353 pyrimidin-4-yl-4- 12.05 (s, 1 H), 8.48 (s, 1 H), 8.16 (d, J = 6.4Hz, piperidyl)-1H-pyrrolo[2,3- 1 H), 7.85-7.79 (m, 2 H), 7.30 (d, J =2.4 Hz, c]pyridine-4-carboxamide 1 H), 6.87 (d, J = 6.4 Hz, 1 H), 6.68(d, J = 2.8 Hz, 1 H), 4.38-4.34 (m, 2 H), 4.10-4.08 (m, 1 H), 3.53 (s, 3H), 3.25-3.04 (m, 2 H), 1.90-1.87 (m, 2 H), 1.46-1.43 (m, 2 H). 1496-methyl-N-[1-(5- ¹H NMR (400 MHz, DMSO-d6): δ 367methylpyrimidin-2-yl)-4- 12.03 (s, 1 H), 8.20 (s, 1 H), 7.80-7.78 (m, 2H), piperidyl]-7-oxo-1H- 7.28 (d, J = 2.4 Hz, 1 H), 6.67 (d, J = 2.8 Hz,pyrrolo[2,3-c]pyridine-4- 1 H), 4.56-4.53 (m, 2 H), carboxamide4.10-3.90 (m, 1 H), 3.51 (s, 3 H), 3.03-2.96 (m, 2 H), 2.06 (s, 3 H),1.85-1.83 (m, 2 H), 1.44-1.39 (m, 2 H). 150 6-methyl-N-[1-(4- ¹H NMR(400 MHz, DMSO-d6): δ 367 methylpyrimidin-2-yl)-4- 12.03 (s, 1 H), 8.19(d, J = 5.2 Hz, 1 H), piperidyl]-7-oxo-1H- 7.81-7.78 (m, 2 H), 7.28 (s,1 H), 6.67 (s, 1 H), pyrrolo[2,3-c]pyridine-4- 6.47 (d, J = 5.2 Hz, 1H), 4.63-4.59 (m, 2 carboxamide H), 4.05-4.02 (m, 1 H), 3.51 (s, 3 H),2.99 (t, J = 11.6 Hz, 2 H), 2.25 (s, 3 H), 1.86-1.84 (m, 2 H), 1.47-1.42(m, 2 H). 151 6-methyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 353pyrazin-2-yl-4-piperidyl)- 12.07 (s, 1 H), 8.37 (d, J = 1.2 Hz, 1 H),8.09 (d, 1H-pyrrolo[2,3-c]pyridine- J = 0.8 Hz, 1 H), 7.89-7.79 (m, 3H), 4-carboxamide 7.31 (s, 1 H), 6.71 (s, 1 H), 4.36-4.32 (m, 2 H),4.10-4.08 (m, 1 H), 3.54 (s, 3 H). 3.06 (t, J = 11.6 Hz, 2 H), 1.91-1.89(m, 2 H), 1.56-1.47 (m, 2 H). 152 N-[1-(5-cyanopyrimidin-2- ¹H NMR (400MHz, DMSO-d6): δ 378 yl)-4-piperidyl]-6-methyl- 12.06 (s, 1 H), 8.74 (s,2 H), 7.87 (d, J = 7.2 Hz, 7-oxo-1H-pyrrolo[2,3- 1 H), 7.79 (s, 1 H),7.29-7.28 (m, 1 H), c]pyridine-4-carboxamide 6.66 (s, 1 H), 4.65-4.61(m, 2 H), 4.11-4.09 (m, 1 H), 3.52 (s, 3 H), 3.24-3.18 (m, 2 H),1.94-1.91 (m, 2 H), 1.47-1.42 (m, 2 H). 153 6-methyl-7-oxo-N-[1-[4- ¹HNMR (400 MHz, DMSO-d6): δ 421 (trifluoromethyl)pyrimidin- 12.04 (s, 1H), 8.66-8.63 (m, 1 H), 7.84-7.78 (m, 2-yl]-4-piperidyl]-1H- 2 H), 7.28(d, J = 2.8 Hz, 1 H), pyrrolo[2,3-c]pyridine-4- 6.98-6.94 (m, 1 H), 6.66(d, J = 2.8 Hz, 1 H), carboxamide 4.58-4.55 (m, 2 H), 4.08-4.06 (m, 1H), 3.50 (s, 3 H), 3.15-3.12 (m, 2 H), 1.91-1.86 (m, 2 H), 1.49-1.41 (m,2 H). 154 N-[1-(5-fluoropyrimidin-2- ¹H NMR (400 MHz, DMSO-d6): δ 371yl)-4-piperidyl]-6-methyl- 12.05 (s, 1 H), 8.43 (s, 2 H), 7.84-7.79 (m,2 H), 7-oxo-1H-pyrrolo[2,3- 7.29-7.28 (m, 1 H), 6.67 (s, 1 H),c]pyridine-4-carboxamide 4.52-4.48 (m, 2 H), 4.06-4.03 (m, 1 H), 3.51(s, 3 H), 3.05 (t, J = 11.6 Hz, 2 H), 1.87-1.84 (m, 2 H), 1.48-1.40 (m,2 H). 155 6-methyl-7-oxo-N-(1- ¹H NMR (400 MHz, DMSO-d6): δ 353pyridazin-3-yl-4- 12.07 (s, 1 H), 8.53 (d, J = 3.6 Hz, 1 H),piperidyl)-1H-pyrrolo[2,3- 7.87-7.82 (m, 2 H), 7.39-7.29 (m, 3 H), 6.71(s, c]pyridine-4-carboxamide 1 H), 4.40-4.36 (m, 2 H), 4.11-4.10 (m, 1H), 3.54 (s, 3 H), 3.08 (t, J = 11.6 Hz, 2 H), 1.92-1.89 (m, 2 H),1.58-1.50 (m, 2 H). 156 N-[1-(4-cyanopyrimidin-2- ¹H NMR (400 MHz,DMSO-d6): δ 378 yl)-4-piperidyl]-6-methyl- 12.08 (s, 1 H), 8.66 (d, J =4.5 Hz, 1 H), 7-oxo-1H-pyrrolo[2,3- 7.88-7.82 (m, 2 H), 7.32 (s, 1 H),7.15 (d, J = 4.5 Hz, c]pyridine-4-carboxamide 1 H), 6.70 (s, 1 H),4.57-4.54 (m, 2 H), 4.12-4.10 (m, 1 H), 3.55 (s, 3 H), 3.16 (t, J = 11.6Hz, 2 H), 1.95-1.92 (m, 2 H), 1.53-1.45 (m, 2H). 157N,6-dimethyl-7-oxo-N-[(1- ¹H NMR (400 MHz, DMSO-d₆) δ 381pyrimidin-2-yl-4- 12.14-12.09 (m, 2H), 8.31 (d, J = 4.7 Hz, 2H),piperidyl)methyl]-1H- 7.41 (s, 1H), 7.35-7.29 (m, 1H), 6.56 (t,pyrrolo[2,3-c]pyridine-4- J = 4.7 Hz, 1H), 6.23-6.16 (m, 1H),carboxamide 4.62 (d, J = 12.8 Hz, 2H), 3.53 (s, 3H), 3.38-3.33 (m, 2H),2.98 (s, 3H), 2.92-2.81 (m, 2H), 2.05-2.00 (m, 1H), 1.68-1.63 (m, 2H),1.04-0.99 (m, 2H). 158 N,6-dimethyl-7-oxo-N-[(1- 1H NMR (400 MHz,DMSO-d6) δ 381 pyrimidin-4-yl-4- 12.08 (s, 1H), 8.44 (s, 1H), 8.12 (d, J= 6.2 Hz, piperidyl)methyl]-1H- 1H), 7.39 (s, 1H), 7.32 (d, J = 2.8 Hz,1H), pyrrolo[2,3-c]pyridine-4- 6.78 (d, J = 6.3 Hz, 1H), 6.26-6.11 (m,carboxamide 1H), 4.36 (d, J = 13.0 Hz, 2H), 3.52 (s, 3H), 3.41-3.32 (m,2H), 2.97 (s, 3H), 2.95-2.83 (m, 2H), 2.22-1.95 (m, 1H), 1.79-1.51 (m,2H), 1.21-0.96 (m, 2H).

Example 159 6-allyl-N-methyl-7-oxo-N-[1-[4-(trioromethyl)pyrimidin-2-yl]-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: 6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid

Sodium hydride, 60% in mineral oil (870 mg, 21.65 mmol) was added in 3portions to a cooled (0° C.) solution of methyl7-oxo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridine-4-carboxylate(Intermediate B, 5.0 g, 14.43 mmol) in DMF (70 mL). The reaction wasstirred for 30 min at room temperature and 3-bromoprop-1-ene (1.37 mL,15.88 mmol) was added. The reaction was warmed (50° C.) and stirring wascontinued for 3 h. The reaction was quenched with minimal methanol, andthen water (100 mL) was added. The mixture was extracted with ethylacetate (3×50 mL). The combined organic extracts were dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (0-5% methanol: dichloromethane)yielding 1.96 of ester intermediate as a white solid that wasimmediately carried forward.

Potassium hydroxide (1.42 g, 25.4 mmol) in water (10 mL) was added to asolution of methyl6-allyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylate(1.96 g, 1.0 equiv., 5.07 mmol) in methanol (25 mL). The reaction wasstirred at 45° C. for 1 h. The reaction was then cooled to roomtemperature, and the methanol was evaporated under reduced pressure. Theaqueous solution was acidified to pH 2 using 3N hydrochloric acid, andthe resulting precipitate was collected by filtration. The filter cakewas washed with water and dried, yielding title compound (1.18 g, 37%).LCMS M/Z (M+H) 219.

Step 2:6-allyl-N-methyl-7-oxo-N-[[4-(trifluoromethyl)pyrimidin-2-yl]-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To an 8 mL vial was added6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Step 1.50 mg,0.23 mmol), N,N-dimethylformamide (1 mL), HATU (1.05 equiv., 0.24 mmol),and triethylamine (4 equiv., 0.92 mmol). The reaction vial was cappedand vortexed for one minute.N-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-aminehydrochloride (62 mg, 0.27 mmol, as prepared in example 139) was addedand the reaction vial shaken at room temperature overnight. The reactionmixture was diluted with dichloromethane and washed with water. Theorganic solution was then concentrated under reduced pressure and theresidue was purified by HPLC (20-60% ACN/0.1% NH4OH in H2O) yieldingtitle compound (32 mg, 36%). ¹H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H),8.47 (d, J=1.2 Hz, 1H), 8.15 (d, J=6.2 Hz, 1H), 7.43-7.25 (m, 2H), 6.85(dd, J=6.4, 1.3 Hz, 1H), 6.24 (t, J=2.3 Hz, 1H), 5.99 (ddt, J=17.2,10.5, 5.3 Hz, 1H), 5.17 (dq, J=10.3, 1.4 Hz, 1H), 5.13-5.01 (m, 1H),4.72-4.58 (m, 2H), 4.51 (d, J=13.1 Hz, 2H), 4.33 (s, 1H), 2.79 (s, 5H),1.72 (td, J=11.4, 10.2, 3.8 Hz, 4H). LCMS M/Z (M+H) 393.

The following compounds were prepared in a similar fashion to Example159. Examples 160-168

Example Compound Name NMR m/z 160 6-allyl-N-[1-(2- 1H NMR (400 MHz,DMSO-d6) δ 12.15 (s, 1H), 418 cyanopyrimidin-4- 8.67 (d, J = 4.8 Hz,1H), 7.43-7.22 (m, 2H), yl)-4-piperidyl]-N- 6.99 (d, J = 4.8 Hz, 1H),6.30-6.19 (m, 1H), methyl-7-oxo-1H- 6.12-5.89 (m, 1H), 5.25-5.13 (m,1H), 5.13-5.01 (m, 1H), pyrrolo[2,3- 4.77 (d, J = 13.0 Hz, 2H), 4.64 (d,J = 5.4 Hz, 2H), c]pyridine-4- 4.36 (s, 1H), 2.93 (s, 2H), 2.80 (s, 3H),carboxamide 1.90-1.60 (m, 4H). 161 6-allyl-N-methyl-7- 1H NMR (400 MHz,DMSO-d6) δ 12.14 (s, 1H), 393 oxo-N-(1-pyrimidin- 8.47 (d, J = 1.2 Hz,1H), 8.15 (d, J = 6.2 Hz, 1H), 4-yl-4-piperidyl)- 7.43-7.25 (m, 2H),6.85 (dd, J = 6.4, 1.3 Hz, 1H), 1H-pyrrolo[2,3- 6.24 (t, J = 2.3 Hz,1H), 5.99 (ddt, J = 17.2, 10.5, 5.3 Hz, c]pyridine-4- 1H), 5.17 (dq, J =10.3, 1.4 Hz, 1H), carboxamide 5.13-5.01 (m, 1H), 4.72-4.58 (m, 2H),4.51 (d, J = 13.1 Hz, 2H), 4.33 (s, 1H), 2.79 (s, 514), 1.72 (td, J =11.4, 10.2, 3.8 Hz, 4H). 162 6-allyl-N-[1-(6- 1H NMR (400 MHz, DMSO-d6)δ 12.15 (s, 1H), 423 methoxypyrimidin- 8.23 (d, J = 0.8 Hz, 1H), 7.34(d, J = 2.8 Hz, 1H), 4-yl)-4-piperidyl]-N- 7.30 (s, 1H), 6.24 (d, J =2.7 Hz, 1H), 6.10 (d, J = 0.9 Hz, methyl-7-oxo-1H- 1H), 6.06-5.91 (m,1H), 5.21-5.12 (m, pyrrolo[2,3- 1H), 5.12-5.01 (m, 1H), 4.64 (dt, J =5.5, 1.5 Hz, c]pyridine-4- 2H), 4.45 (d, J = 13.1 Hz, 2H), 4.30 (s, 1H),3.81 (s, carboxamide 3H), 3.37-3.25 (m, 1H), 2.78 (s, 5H), 1.74-1.62 (m,4H). 163 6-allyl-N-[1-(6,7- 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H),433 dihydro-5H- 8.30 (s, 1H), 7.35 (d, J = 2.8 Hz, 1H), 7.29 (s, 1H),cyclopenta[d]pyrimidin- 6.23 (d, J = 2.8 Hz, 1H), 6.06-5.91 (m, 1H),4-yl)-4- 5.17 (dq, J = 10.2, 1.4 Hz, 1H), 5.12-5.01 (m, 1H),piperidyl]-N-methyl- 4.67-4.60 (m, 2H), 4.51 (d, J = 13.1 Hz, 2H), 3.30(s, 7-oxo-1H- 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.94-2.85 (m, 2H),pyrrolo[2,3- 2.79 (s, 3H), 2.72 (dd, J = 15.7, 7.8 Hz, 2H),c]pyridine-4- 2.01-1.88 (m, 2H), 1.84-1.70 (m, 4H). carboxamide 1646-allyl-N-methyl-7- 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 461oxo-N-[1-[6- 8.61 (d, J = 1.1 Hz, 1H), 7.38-7.27 (m, 3H),(trifluoromethyl)pyrimidin- 6.25 (d, J = 2.7 Hz, 1H), 6.06-5.92 (m, 1H),4-yl]-4- 5.22-5.13 (m, 1H), 5.12-5.02 (m, 1H), 4.68-4.60 (m, 2H),piperidyl]-1H- 4.41-4.36 (m, 1H), 3.35-3.23 (m, 2H), 2.96 (s,pyrrolo[2,3- 2H), 2.79 (s, 3H), 1.79-1.72 (m, 4H). c]pyridine-4-carboxamide 165 6-allyl-N-[1-(2,6- 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s,1H), 421 dimethylpyrimidin- 7.38-7.27 (m, 2H), 6.53 (s, 1H), 6.28-6.21(m, 4-yl)-4-piperidyl]-N- 1H), 6.06-5.91 (m, 1H), 5.21-5.13 (m, 1H),methyl-7-oxo-1H- 5.12-5.01 (m, 1H), 4.64 (dt, J = 5.4, 1.6 Hz, 2H),pyrrolo[2,3- 4.51 (d, J = 13.1 Hz, 2H), 4.31 (s, 1H), 2.81-2.76 (m,c]pyridine-4- 5H), 2.31 (s, 3H), 2.20 (s, 3H), 1.75-1.61 (m, 4H).carboxamide 166 6-allyl-N-methyl-7- 1H NMR (400 MHz, DMSO-d6) δ 12.15(s, 1H), 435 oxo-N-[1-(6- 8.39 (d, J = 1.1 Hz, 1H), 7.38-7.28 (m, 2H),propylpyrimidin-4- 6.70 (d, J = 1.3 Hz, 1H), 6.24 (d, J = 2.8 Hz, 1H),yl)-4-piperidyl]-1H- 6.06-5.91 (m, 1H), 5.21-5.13 (m, 1H), 5.12-5.01 (m,pyrrolo[2,3- 1H), 4.67-4.60 (m, 2H), 4.52 (d, J = 12.9 Hz, 2H),c]pyridine-4- 3.35-3.25 (m, 16H), 2.85-2.76 (m, 5H), carboxamide2.56-2.42 (m, 2H), 1.76-1.57 (m, 6H), 0.98-0.84 (m, 3H). 1676-allyl-N-[1-(6- 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 435isopropylpyrimidin- 8.40 (d, J = 1.0 Hz, 1H), 7.38-7.28 (m, 2H),4-yl)-4-piperidyl]-N- 6.68 (d, J = 1.2 Hz, 1H), 6.24 (d, J = 2.8 Hz,1H), methyl-7-oxo-1H- 6.06-5.91 (m, 1H), 5.21-5.13 (m, 1H), 5.12-5.01(m, pyrrolo[2,3- 1H), 4.67-4.50 (m, 4H), 3.30 (d, J = 19.9 Hz, 16H),c]pyridine-4- 2.86-2.71 (m, 5H), 1.77-1.66 (m, 4H), 1.17 (d, J = 6.9 Hz,carboxamide 6H). 168 6-allyl-N-[1-(2- 1H NMR (400 MHz, DMSO-d6) δ 12.15(s, 1H), 447 cyclopropyl-6- 7.37-7.27 (m, 2H), 6.47 (s, 1H), 6.24 (d, J= 2.7 Hz, methyl-pyrimidin-4- 1H), 5.99 (ddt, J = 17.2, 10.5, 5.4 Hz,1H), yl)-4-piperidyl]-N- 5.17 (dq, J = 10.3, 1.4 Hz, 1H), 5.06 (dq, J =17.2, 1.6 Hz, methyl-7-oxo-1H- 1H), 4.64 (dt, J = 5.6, 1.6 Hz, 2H), 4.48(d, J = 13.1 Hz, pyrrolo[2,3- 2H), 4.30 (s, 0H), 2.90-2.67 (m, 5H), 2.18(s, c]pyridine-4- 3H), 1.89 (tt, J = 7.9, 4.9 Hz, 1H), 1.74-1.60 (m,carboxamide 4H), 0.93-0.79 (m, 4H).

Example 1696-allyl-N-methyl-7-oxo-N-[1-(6-pyrazol-1-ylpyrazin-2-yl)-4-piperidyl]-1H-pyrrolo[2,3c]pyridine-4-carboxamide

Step 1: 2-chloro-6-(1H-pyrazol-1-yl)pyrazine

To a 40 mL vial was added 2,6-dichloropyrazine (4.0 g, 26.9 mmol),1H-pyrazole (1.8 g, 26.9 mmol), potassium carbonate (7.4 g, 53.7 mmol),and 10 mL of N,N-dimethylacetamide. The reaction was capped and shakenat 50° C. for 2 hours, then cooled to room temperature and diluted withethyl acetate. The organic was then washed with water, and concentratedunder reduced pressure. The crude product was purified by flash column(10-35% Ethyl Acetate: Heptanes) yielding title compound as a whitesolid (1.51 g, 31%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.24-9.12 (m, 2H),8.80-8.68 (m, 2H), 8.68-8.54 (m, 2H), 7.96 (dd, J=1.7, 0.7 Hz, 2H),6.74-6.63 (m, 2H), 3.38-3.24 (m, 1H). LCMS M/Z (M+H) 281.

Step 2:6-allyl-N-methyl-7-oxo-N-(piperidin-4-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride

To a round bottom flask was added6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (2.3 g, 10.5mmol Example 159, step 1) followed by N,N-dimethylformamide (20 mL),HATU (4.3 g, 11.1 mmol), triethylamine (5.9 mL, 42.2 mmol), andtert-butyl 4-(methylamino)-piperidine-1-carboxylate (2.9 g, 13.7 mmol).The reaction was stirred for 1 h, then was diluted with ethyl acetate,and washed with water. The organic was concentrated under reducedpressure. The crude product was purified by flash column (0-10%dichloromethane: methanol) yielding boc protected product.

The product was then taken up with 20 mL methanol, and 10 mL of 4N HClin dioxane was added. The reaction was stirred at r.t. for 1 h, at whichtime mixture was concentrated under reduced pressure yielding product asHCl salt (2.0 g, 55% over two steps). The crude amine was carried onwithout further purification. LCMS M/Z (M+H) 315.

Step 3:6-allyl-N-methyl-7-oxo-N-[1-(6-pyrazol-1-ylpyrazin-2-yl)-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a 4 mL vial was added6-allyl-N-methyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride (40 mg, 0.11 mmol) followed by2-chloro-6-pyrazol-1-yl-pyrazine (21 mg, 0.11 mmol),diisopropylethylamine (0.08 mL, 0.46 mmol), and 0.16 mL. The reactionwas capped and shaken at 90° C. overnight. The reaction was cooled toroom temperature, diluted with ethyl acetate, and washed with water. Theorganic was concentrated under reduced pressure, and the residue waspurified by HPLC (20-60% ACN/0.1% NH4OH in H2O) yielding title compound(10 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.59 (dd,J=2.6, 0.7 Hz, 1H), 8.38-8.17 (m, 2H), 7.82 (dd, J=1.7, 0.7 Hz, 1H),7.42-7.21 (m, 2H), 6.57 (dd, J=2.6, 1.7 Hz, 1H), 6.25 (dd, J=2.8, 1.5Hz, 1H), 6.07-5.89 (m, 1H), 5.24-5.13 (m, 1H), 5.13-5.02 (m, 1H),4.67-4.61 (m, 2H), 4.57 (d, J=13.2 Hz, 2H), 4.35 (s, 1H), 3.04-2.86 (m,2H), 2.81 (s, 3H), 1.95-1.68 (m, 4H). LCMS M/Z (M+H) 459.

Example 1706-aryl-N-methyl-7-oxo-N-[1-(6-pyrazol-1-ylpyrimidin-4-yl)-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1 tert-butyl(1-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(methyl)carbamate

To a solution of tert-butyl(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl) carbamate (600 mg,1.84 mmol) in DMF (10 mL) was added 1H-pyrazole (150 mg, 2.20 mmol) andcesium carbonate (1.2 g, 3.67 mmol). After addition, the reactionmixture was heated at 80° C. for 12 h, at which time LCMS indicated thereaction had gone to completion. After cooled, the solid was removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate (50 mL), washed with water (2×30mL), dried over sodium sulfate and concentrated to give the crude titlecompound (500 mg, 76% yield) as a yellow solid.

Step 2 1-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-N-methylpiperidin-4-aminehydrochloride

To a solution of tert-butyl(1-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(methyl) carbamate(500 mg, 1.39 mmol) in ethyl acetate (10 mL) was added hydrogen chloride(2 N in ethyl acetate, 10 mL) at 0° C. After addition, the mixture wasstirred at ambient temperature for 2 h, at which time LCMS indicated thereaction had gone to completion. The solution was concentrated underreduced pressure to give the crude title compound (400 mg, 97% yield) asa white solid.

Step 36-allyl-N-methyl-7-oxo-N-[1-(6-pyrazol-1-ylpyrimidin-4-yl)-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a solution of1-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-N-methylpiperidin-4-aminehydrochloride (216 mg, 0.73 mmol) in DMF (4 mL) was added6-allyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid(80 mg, 0.37 mmol), N-ethyl-N-isopropylpropan-2-amine (142 mg, 1.1 mmol)and HATU (181 mg, 0.48 mmol). After addition, the mixture was stirred atambient temperature for 1.5 h, at which time LCMS indicated that thereaction had gone to completion. The solvent was removed under reducepressure. The residue was dissolved in ethyl acetate (20 mL), washedwith brine (2×15 mL) and concentrated. The crude product was purified byreverse phase chromatography (acetonitrile 40%/0.1% NH₄OH in water) togive the title compound (12.8 mg, 8% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆): δ 12.19 (s, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 7.91(s, 1H), 7.34 (d, J=11.6 Hz, 2H), 7.24 (s, 1H), 6.63 (s, 1H), 6.24 (s,1H), 5.99-5.94 (m, 1H), 5.16 (d, J=10.0 Hz, 1H), 5.06 (d, J=17.2 Hz,1H), 4.64-4.40 (m, 5H), 3.03 (s, 2H), 2.78 (s, 3H), 1.79 (s, 4H). LCMSM/Z (M+H) 459.1.

Example 1716-methyl-7-oxo-N-(1-phenyl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: tert-butyl (1-phenylpiperidin-4-yl)carbamate

To a solution of tert-butyl piperidin-4-ylcarbamate (420 mg, 1.96 mmol)in dry xylene (8 mL) was added 1-iodo-4-methylbenzene (400 mg, 1.96mmol), sodium tert-butoxide (564 mg, 5.88 mmol), Pd₂(dba)₃ (10 mg) andxantphos (15 mg). With nitrogen protection, the reaction mixture washeated at 120° C. under microwave conditions for 30 min, at which timeLCMS indicated the reaction had gone to completion. The mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (Hexanes/ethyl acetate=5:1) to give the titlecompound (100 mg, 17.5% yield) that was used directly in step 2.

Step 2 1-phenylpiperidin-4-amine hydrochloride

To a solution of tert-butyl (1-phenylpiperidin-4-yl)carbamate (100 mg,0.35 mmol) in ethyl acetate (10 mL) was added Hydrogen chloride (2 N inEthyl acetate, 10 mL). The reaction mixture was stirred at ambienttemperature for 30 min and then concentrated under reduced pressure togive the crude title compound as hydrogen chloride salt (60 mg, 78%yield). This material was used directly in the next step.

Step 36-methyl-7-oxo-N-(1-phenyl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a solution of 1-phenylpiperidin-4-amine hydrochloride (60 mg, 0.28mmol) in DMF (3 mL) was added6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid(Intermediate C) (65 mg, 0.34 mmol), HATU (128 mg, 0.34 mmol) anddiisopropylethylamine (1 mL). The reaction mixture was stirred atambient temperature for 4 h, at which time LCMS indicated that thereaction had gone to completion. The mixture was concentrated underreduced pressure. The residue was diluted with ethyl acetate (15 mL) andwashed with water (2×10 mL). The organic solution was concentrated underreduced pressure and the residue was purified by preparative HPLC(basic-acetonitrile: water (10 nM ammonia)25%-55%) to give the titlecompound (20 mg, 15% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6):δ 12.03 (s, 1H), 7.85-7.79 (m, 2H), 7.28 (s, 1H), 7.19-7.15 (m, 2H),6.93-6.91 (m, 2H), 6.72-6.65 (m, 2H), 3.92-3.90 (m, 1H), 3.71-3.68 (m,2H), 3.51 (s, 3H), 2.78 (t, J=11.6 Hz, 2H), 1.86-1.84 (m, 2H), 1.63-1.55(m, 2H). LCMS M/Z (M+H) 351.1.

The following compounds were prepared in a similar fashion to Example168. Examples 172-180

Example Compound Name NMR m/z 172 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz,DMSO-d6): δ 365 (1-phenyl-4-piperidyl)- 12.18-12.10 (br. s., 1 H), 7.41(s, 1 H), 7.34 (s, 1 H), 1H-pyrrolo[2,3- 7.23-7.17 (m, 2 H), 6.93 (d, J= 8.0 Hz, 2 H), 6.75 (t, c]pyridine-4- J = 7.4 Hz, 1 H), 6.22 (s, 1 H),4.28-4.15 (m, 1 carboxamide H), 3.77-3.71 (m, 2 H), 3.53 (s, 3 H), 2.83(s, 3 H), 2.68-2.60 (m, 2 H), 1.93-1.85 (m, 2 H), 1.74-1.72 (m, 2 H) 173N,6-dimethyl-N-[1-(m- ¹H NMR (400 MHz, CD₃OD): δ 7.43-7.41 (m, 2 379tolyl)-4-piperidyl]-7- H), 7.12 (t, J = 7.6 Hz, 1 H), 6.84-6.80 (m, 2H), oxo-1H-pyrrolo[2,3- 6.70 (d, J = 7.2 Hz, 1 H), 6.38 (d, J = 2.4 Hz,1 c]pyridine-4- H), 3.80-3.60 (m, 5 H), 3.00 (s, 3 H), carboxamide2.93-2.47 (m, 3 H), 2.30 (s, 3 H), 2.13-2.02 (m, 2 H), 1.94-1.82 (m, 2H). 174 N,6-dimethyl-7-oxo-N- ¹ NMR (400 MHz, CD₃OD): δ 7.90-7.71 (m, 4432 [1-[3- H), 7.43-7.39 (m, 2 H), 6.37 (d, J = 2.4 Hz, 1 H),(trifluoromethyl)phenyl]- 3.86-3.83 (m, 2 H), 3.66 (s, 4 H), 3.03 (s, 3H), 4-piperidyl]-1H- 2.47-2.39 (m, 2 H), 2.16-2.13 (m, 2 H).pyrrolo[2,3-c]pyridine-4- carboxamide 175 N,6-dimethyl-7-oxo-N- ¹ H NMR(400 MHz, CD₃OD): δ 7.39-7.35 (m, 3 433 [1-[4- H), 7.18-7.14 (m, 2 H),7.04 (d, J = 7.2 Hz, 1 H), (trifluoromethyl)phenyl]- 6.35 (d, J = 2.8Hz, 1 H), 3.91-3.79 (m, 2 H), 4-piperidyl]-1H- 3.65 (s, 3 H), 3.36-3.34(m, 1 H), 2.97 (s, 3 H), pyrrolo[2,3-c]pyridine-4- 2.84-2.74 (m, 2 H),2.07-2.01 (m, 2 H), carboxamide 1.99-1.87 (m, 2 H). 176N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, CD₃OD): δ 7.47-7.36 (m, 2 379[1-(p-tolyl)-4-piperidyl]- H), 7.06 (d, J = 8.0 Hz, 2 H), 6.91 (d, J =7.2 Hz, 1H-pyrrolo[2,3- 2 H), 6.38 (d, J = 3.2 Hz, 1 H), 3.70-3.67 (m, 5c]pyridine-4- H), 3.01 (s, 3 H), 2.87-2.53 (m, 3 H), 2.25 (s, 3carboxamide H), 2.13-2.02 (m, 2 H), 1.89-1.83 (m, 2 H). 177N-[1-(3-ethylphenyl)-4- ¹H NMR (400 MHz, CD₃OD): δ 7.43-7.42 (m, 2 393piperidyl]-N,6-dimethyl- H), 7.18-7.12 (m, 1 H), 6.87-6.80 (m, 2 H),7-oxo-1H-pyrrolo[2,3- 6.76-6.71 (m, 1 H), 6.38 (d, J = 2.8 Hz, 1 H),c]pyridine-4- 3.85-3.70 (m, 2 H), 3.68 (s, 3 H), 3.01 (s, 3 H),carboxamide 2.89-2.50 (m, 5 H), 2.13-2.03 (m, 2 H), 1.95-1.84 (m, 2 H),1.22 (t, J = 8.0 Hz, 3 H). 178 N-[1-(4-ethylphenyl)-4- ¹H NMR (400 MHz,CD₃OD): δ 7.43-7.41 (m, 2 393 piperidyl]-N,6-dimethyl- H), 7.09 (d, J =8.4 Hz, 2 H), 6.93 (d,J = 6.8 Hz, 7-oxo-1H-pyrrolo[2,3- 2 H), 6.38 (d, J= 2.4 Hz, 1 H), 3.75-3.60 (m, 5 c]pyridine-4- H), 3.01 (s, 3 H),2.80-2.49 (m, 5 H), carboxamide 2.10-2.02 (m, 2 H), 1.90-1.79 (m, 2 H),1.20 (t, J = 7.6 Hz, 3H). 179 N-[1-(3- ¹ H NMR (400 MHz, CD₃OD): δ7.43-7.41 (m, 2 407 isopropylphenyl)-4- H), 7.16 (t, J = 7.8 Hz, 1 H),6.87-6.72 (m, 3 H), piperidyl]-N,6-dimethyl- 6.38 (d, J = 3.2 Hz, 1 H),3.83-3.71 (m, 2 H), 7-oxo-1H-pyrrolo[2,3- 3.68 (s, 3 H), 3.01 (s, 3 H),2.97-2.46 (m, 4 H), c]pyridine-4- 2.13-2.03 (m, 2 H), 1.95-1.80 (m, 2H), 1.24 (d, carboxamide J = 7.2 Hz, 6 H). 180 N-[1-(4- ¹H NMR (400 MHz,CD₃OD): δ 7.47-7.34 (m, 2 407 isopropylphenyl)-4- H), 7.12 (d, J = 8.4Hz, 2 H), 6.94 (d, J = 7.2 Hz, piperidyl]-N,6-dimethyl- 2 H), 6.38 (d, J= 3.2 Hz, 1 H), 3.76-3.60 (m, 5 7-oxo-1H-pyrrolo[2,3- H), 3.01 (s, 3 H),2.97-2.45 (m, 4 H), c]pyridine-4- 2.13-2.02 (m, 2 H), 1.90-1.82 (m, 2H), 1.22 (d, J = 6.8 Hz, carboxamide 6 H).

Example 181N,6-dimethyl-N-[2-(1-methyl-4-piperidyl)ethyl]-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: tert-butyl4-[2-[(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]ethyl]piperidine-1-carboxylate

HATU (988 mg, 2.6 mmol) was added to a stirred mixture of6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (IntermediateC) (500 mg, 2.6 mmol), tert-butyl4-(2-aminoethyl)piperidine-1-carboxylate (713 mg, 3.1 mmol), anddiisopropylethylamine (1.0 g, 7.8 mmol) in DMF (10 mL). The reactionmixture was stirred at room temperature for 16 h, at which time LCMSindicated that the reaction had gone to completion. The reaction mixturewas partitioned between ethyl acetate (50 mL) and water (15 mL). Theseparated organic solution was washed with brine (2×10 mL), dried oversodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography column(dichloromethane:methanol=10:1) to afford the title compound (800 mg,72.4% yield) as a yellow solid. LCMS M/Z (M+H) 402.9.

Step 2: tert-butyl4-[2-[[6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carbonyl]amino]ethyl]piperidine-1-carboxylate

Sodium hydride (60%, 119 mg, 3.0 mmol) was added to a stirred and cooled(0° C.) solution of tert-butyl4-[2-[(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]ethyl]piperidine-1-carboxylate(800 mg, 2.0 mmol) in DMF (10 mL). Stirring was continued for 1 h atroom temperature before 4-methylbenzene-1-sulfonyl chloride (455 mg, 2.4mmol) was added. The reaction mixture was then stirred at roomtemperature for 1 h and quenched by addition of saturated aqueousammonium chloride (2 mL). The reaction mixture was partitioned betweenethyl acetate (150 mL) and water (50 mL). The organic layer was washedwith brine (10 mL×2), dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatography(petroleum ether: ethyl acetate=1:2) to afford the title compound (500mg, 45.0% yield) as a white solid. LCMS M/Z (M+H) 556.8.

Step 3: tert-butyl4-[2-[methyl-[6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carbonyl]amino]ethyl]piperidine-1-carboxylate

Sodium hydride (60%, 54 mg, 1.4 mmol) was added to a stirred and cooled(0° C.) solution of tert-butyl4-[2-[[6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carbonyl]amino]ethyl]piperidine-1-carboxylate(Step 2, 500 mg, 0.9 mmol) in DMF (10 mL). Stirring was continued for 1h at room temperature before iodomethane (153 mg, 1.1 mmol) was added.The reaction mixture was then stirred at room temperature for 1 h andquenched by addition of saturated aqueous ammonium chloride (2 mL). Thereaction mixture was partitioned between ethyl acetate (120 mL) andwater (30 mL). The organic layer was washed with brine (10 mL×2), driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (petroleum ether: ethylacetate=1:1) to afford the title compound (350 mg, 68.3% yield) as ayellow solid. LCMS M/Z (M+H) 571.2.

Step 4:N,6-dimethyl-7-oxo-N-[2-(4-piperidyl)ethyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine4carboxamide hydrogen chloride

A mixture of tert-butyl4-[2-[methyl-[6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carbonyl]amino]ethyl]piperidine-1-carboxylate(350 mg, 0.6 mmol) in 4 N Hydrogen chloride/ethyl acetate, (40 mmol, 10mL) was stirred at room temperature for 2 h. The solvent wasconcentrated under reduced pressure to give the crude title compound asa yellow solid that was carried on to the next step. LCMS M/Z (M+H)471.8.

Step 5:N,6-dimethyl-N-[2-(1-methyl-4-piperidyl)ethyl]-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamide

A mixture ofN,6-dimethyl-7-oxo-N-[2-(4-piperidyl)ethyl]-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamidehydrogen chloride (100 mg, 0.2 mol) and paraformaldehyde (7 mg, 0.2mmol) in methanol (5 mL) was heated at 70° C. for 16 h. The solution wascooled to 0° C. and then sodium borohydride (12 mg, 0.3 mmol) was added.After addition, stirring was continued for 1 h at room temperature. Thereaction mixture was quenched by addition of saturated aqueous ammoniumchloride (5 mL). The resulting mixture was partitioned between ethylacetate (30 mL) and water (10 mL). The separated organic solution waswashed with brine (2×5 mL), dried over sodium sulfate and concentratedunder reduced pressure to afford the crude title compound (100 mg, 97.1%yield) as a white solid. LCMS M/Z (M+H) 485.1.

Step 6:N,6-dimethyl-N-[2-(1-methyl-4-piperidyl)ethyl]-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

A mixture ofN,6-dimethyl-N-[2-(1-methyl-4-piperidyl)ethyl]-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamide(100 mg, 0.2 mmol) in methanol (2 mL) and aqueous sodium hydroxidesolution (20% wt/vol, 1 mL) was heated at 100° C. for 16 h. Aftercooling, the mixture was concentrated under reduced pressure and theresidue was purified by preparative HPLC, acetonitrile: water (10 nMammonia), 10%-40%, to give the title compound (10 mg, 14.5% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1H), 7.38-7.30 (m,2H), 6.16 (d, J=3.2 Hz, 1H), 3.50 (s, 3H), 2.90 (s, 3H), 2.65-2.64 (m,2H), 2.06 (s, 3H), 1.73-1.49 (m, 7H), 1.06-1.05 (m, 4H). LCMS M/Z (M+H)331.2.

The following compounds were prepared in a similar fashion to Example181. Examples 182-186

Example Compound Name NMR m/z 182 N-[2-(1-ethyl-4- ¹H NMR (400 MHz,CD₃OD): δ 8.52 (s, 1 H), 345 piperidyl)ethyl]-N,6- 7.41 (d, J = 3.6 Hz,2 H), 6.37 (d, J = 2.4 Hz, 1 dimethyl-7-oxo-1H- H), 3.68-3.50 (m, 7 H),3.13-3.32 (m, 5 H), pyrrolo[2,3-c]pyridine- 3.00-2.70 (m, 2 H),2.14-2.10 (m, 1 H), 4-carboxamide 1.82-1.42 (m, 5 H), 1.34-1.21 (m, 4 H)183 N-[2-(1-isopropyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.51 (s, 1 H), 359piperidyl)ethyl]-N,6- 7.48-7.37 (m, 2 H), 6.38 (s, 1 H), 3.70-3.33 (m,dimethyl-7-oxo-1H- 7 H), 3.10-2.75 (m, 6 H), 2.20-2.00 (m, 1 H),pyrrolo[2,3-c]pyridine- 1.85-1.40 (m, 5 H), 1.38-1.10 (m, 7 H)4-carboxamide 184 N-[2-(1-cyclobutyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.48(s, 1 H), 371 piperidyl)ethyl]-N,6- 7.39-7.38 (m, 2 H), 6.34 (d, J = 3.0Hz, 1 H), dimethyl-7-oxo-1H- 3.84-3.32 (m, 7 H), 3.06 (s, 3 H),pyrrolo[2,3-c]pyridine- 2.82-2.52 (m, 2 H), 2.37-2.25 (m, 2 H),2.19-2.10 (m, 2 4-carboxamide H), 2.08-1.96 (m, 2 H), 1.91-1.77 (m, 2H), 1.73-1.51 (m, 4 H), 1.44-1.16 (m, 2 H). 185 N-[2-[1-(2- ¹H NMR (400MHz, CD₃OD): δ 8.52 (s, 1 H), 375 methoxyethyl)-4- 7.39 (d, J = 2.8 Hz,2 H), 6.34 (d, J = 2.0 Hz, 1 piperidyl]ethyl]-N,6- H), 3.76-3.44 (m, 8H), 3.37 (s, 3 H), dimethyl-7-oxo-1H- 3.22-3.18 (m, 2 H), 3.06 (s, 3 H),2.99-2.53 (m, 3 H), pyrrolo[2,3-c]pyridine- 2.25-1.90 (m, 1 H),1.75-1.25 (m, 6 H). 4-carboxamide 186 N-[2-(1-cyclopropyl-4- ¹H NMR (400MHz, DMSO-d6): δ 11.40 (s, 1 301 piperidyl)ethyl]-N,6- H), 8.86 (s, 1H), 8.30 (s, 1 H), 8.22 (s, 1 H), dimethyl-7-oxo-1H- 4.03 (s, 3 H), 2.50(q, J = 1.6 Hz, 2 H), 2.44 (s, pyrrolo[2,3-c]pyridine- 3 H), 1.05 (t, J= 7.6 Hz, 3 H). 4-carboxamide

Example 187N-[[1-(cyclopentylmethyl)-4-piperidyl]methyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: tert-butyl4-[[methyl-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]methyl]piperidine-1-carboxylate

HATU (4.4 g, 11.7 mmol) was added to a stirred mixture of6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (IntermediateC) (1.5 g, 7.8 mmol), tert-butyl4-(2-aminoethyl)piperidine-1-carboxylate (2.1 g, 9.4 mmol), anddiisopropylethylamine (2.0 g, 15.6 mmol) in DMF (50 mL). After addition,the reaction mixture was stirred at room temperature for 2 h, at whichtime LCMS showed the completion of the reaction. The reaction mixturewas diluted with ethyl acetate (200 mL), and then washed with water (50mL), brine (20 mL×2), dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel chromatography(dichloromethane:methanol=10:1) to afford the title compound (2.3 g,74.2% yield) as a white solid. LCMS M/Z (M+H) 402.9.

Step 2:N,6-dimethyl-7-oxo-N-(4-piperidylmethyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrogen chloride

A mixture of tert-butyl4-[[methyl-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]methyl]piperidine-1-carboxylate(2.3 g, 5.7 mmol) in 4 N hydrogen chloride/ethyl acetate (20 mL) wasstirred at room temperature for 2 h. The solvent was evaporated to givethe crude title compound (1.5 g, 88.2% yield) as a colorless oil. LCMSM/Z (M+H) 303.1.

Step 3:N-[[1-(cyclopentylmethyl)-4-piperidyl]methyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Sodium triacetoxyborohydride (112 mg, 0.53 mmol) was added to a stirredmixture ofN,6-dimethyl-7-oxo-N-(piperidin-4-ylmethyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride (80 mg, 0.24 mmol), cyclopentanecarbaldehyde (39 mg, 0.40mmol) in dichloromethane (10 mL). After addition, the reaction mixturewas stirred at room temperature for 20 h, at which time LCMS showed thecompletion of the conversion. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by preparative HPLC, acetonitrile: water (10 nM ammonia),55%-85%, to give the title compound (8.7 mg, 7.8% yield) as a whitesolid. ¹H NMR (400 MHz, CD₃OD): δ 7.40 (s, 2H), 6.35 (d, J=2.4 Hz, 1H),3.67 (s, 3H), 3.50-3.45 (m, 2H), 2.92 (s, 3H), 2.91-2.89 (m, 2H),2.39-2.32 (m, 2H), 2.20-2.11 (m, 4H), 1.81-1.58 (m, 10H), 1.19-1.12 (m,2H). LCMS M/Z (M+H) 385.20.

The following compounds were prepared in a similar fashion to Example187. Examples 188-206

Example Compound Name NMR m/z 188 N,6-dimethyl-N-[(1- ¹H NMR (400 MHz,DMSO-d6): δ 12.14 (s, 1 317 methyl-4- H), 7.40 (s, 1 H), 7.33 (d, J =2.4 Hz, 1 H), piperidyl)methyl]-7-oxo- 6.17 (d, J = 2.4 Hz, 1 H), 3.52(s, 3 H), 1H-pyrrolo[2,3- 3.32-3.30 (m, 2 H), 2.98 (s, 3 H), 2.75-2.70(m, 2 c]pyridine-4- H), 2.10 (s, 3 H), 1.78-1.75 (m, 3 H), carboxamide1.69-1.45 (m, 3 H), 1.20-0.80 (m, 2 H) 189 N-[(1-cyclobutyl-4- ¹H NMR(400 MHz, CD₃OD): δ 8.50 (s, 1 H), 357 piperidyl)methyl]-N,6- 7.41-7.39(m, 2 H), 6.34 (d, J = 2.8 Hz, 1 H), dimethyl-7-oxo-1H- 3.66 (s, 3 H),3.53-3.34 (m, 5 H), 3.09 (s, 3 pyrrolo[2,3-c]pyridine-4- H), 2.75-2.65(m, 2 H), 2.40-1.75 (m, 9 H), carboxamide 1.70-1.45 (m, 2H) 190N-[(1-isopropyl-4- ¹H NMR (400 MHz, CD₃OD): δ 8.52 (s, 1 H), 345piperidyl)methyl]-N,6- 7.40-7.38 (m, 2 H), 6.33 (d, J = 2.8 Hz, 1 H),dimethyl-7-oxo-1H- 3.64 (s, 3 H), 3.53-3.34 (m, 4 H), 3.08 (s, 3pyrrolo[2,3-c]pyridine-4- H), 3.06-2.88 (m, 2 H), 2.30-1.80 (m, 2 H),carboxamide 1.60 (m, 2 H), 1.40-1.25 (m, 6 H) 191 N-[(1-ethyl-4- ¹H NMR(400 MHz, DMSO-d6): δ 12.07 (s, 1 331 piperidyl)methyl]-N,6- H), 8.24(s, 1 H), 7.91 (t, J = 5.2 Hz, 1 H), dimethyl-7-oxo-1H- 7.77 (s, 1 H),7.30 (s, 1 H), 6.67 (s, 1 H), pyrrolo[2,3-c]pyridine-4- 3.52 (s, 3 H),3.26-3.23 (m, 2 H), 2.91 (d, J = 11.2 Hz, carboxamide 2 H), 2.52 (s, 3H), 2.34-2.31 (m, 1 H), 1.96 (t, J = 10.8 Hz, 2 H), 1.69 (d, J = 11.6Hz, 2 H), 1.46-1.40 (m, 2 H), 1.21-1.14 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3H). 192 N-[(1-cyclopropyl-4- ¹H NMR (400 MHz, DMSO-d6): δ 11.90 (s, 1343 piperidyl)methyl]-N,6- H), 7.16 (s, 1 H), 7.10 (s, 1 H), 5.95 (s, 1H), dimethyl-7-oxo-1H- 3.30 (s, 3 H), 3.07-3.00 (m, 3 H), 2.71 (s, 3pyrrolo[2,3-c]pyridine-4- H), 2.69-2.64 (m, 2 H), 1.88-1.65 (m, 2 H),carboxamide 1.49-1.26 (m, 5 H), 0.16-0.13 (m, 2 H), 0.04-0.01 (m, 2 H).193 N-[[1-(2-methoxyethyl)- ¹H NMR (400 MHz, DMSO-d6): δ 12.08 (s, 1 3614-piperidyl]methyl]-N,6- H), 7.91-7.85 (m, 1 H), 7.79 (s, 1 H), 7.31 (d,dimethyl-7-oxo-1H- J = 2.8 Hz, 1 H), 6.69 (d, J = 2.8 Hz, 1 H),pyrrolo[2,3-c]pyridine-4- 3.54 (s, 3 H), 3.40 (t, J = 6.4 Hz, 2H),carboxamide 3.26 (d, J = 5.2 Hz, 2 H), 3.21 (s, 3 H), 2.82 (d, J = 11.6Hz, 2H), 2.41 (t, J = 6.4 Hz, 2 H), 1.89 (t, J = 10.8 Hz, 2 H), 1.65 (d,J = 11.6 Hz, 2 H), 1.47-1.41 (m, 2 H), 1.24-1.21 (m, 1 H), 1.18-1.09 (m,2 H). 194 N-[(1-benzyl-4- ¹H NMR (400 MHz, CD₃OD): δ 7.40 (s, 1 H), 393piperidyl)methyl]-N,6- 7.39 (s, 1 H), 7.31-7.28 (m, 5 H), 6.34 (d, J =2.4 Hz, dimethyl-7-oxo-1H- 1 H), 3.67 (s, 3 H), 3.52-3.50 (m, 4pyrrolo[2,3-c]pyridine-4- H), 3.06 (s, 3 H), 2.93-2.85 (m, 2 H),carboxamide 2.10-2.04 (m, 2 H), 1.67-1.02 (m, 5 H). 195N,6-dimethyl-N-[[1-(o- ¹H NMR (400 MHz, CD₃OD): δ 7.40-7.38 (m, 407tolylmethyl)-4- 2H), 7.23-7.15 (m, 4 H), 6.34 (d, J = 2.8 Hz,piperidyl]methyl]-7-oxo- 1 H), 3.66 (s, 3 H), 3.49-3.45 (m, 4 H),1H-pyrrolo[2,3- 3.08 (s, 3 H), 2.96-2.93 (m, 2 H), 2.35 (s, 3 H),c]pyridine-4- 2.06-2.00 (m, 2 H), 1.76-1.24 (m, 5 H). carboxamide 196N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 407[[1-(p-tolylmethyl)-4- H), 7.38 (s, 1 H), 7.32 (d, J = 2.4 Hz, 1 H),piperidyl]methyl]-1H- 7.12-7.08 (m, 4 H), 6.17 (d, J = 3.2 Hz, 1 H),pyrrolo[2,3-c]pyridine-4- 3.52 (s, 3 H), 3.33-3.30 (m, 4 H), 2.93 (s, 3carboxamide H), 2.74-2.71 (m, 2 H), 2.26 (s, 3 H), 1.88-1.85 (m, 2 H),1.66-1.54 (m, 3 H), 1.09-1.05 (m, 2 H). 197 N,6-dimethyl-7-oxo-N- ¹H NMR(400 MHz, DMSO-d6): δ 12.09 (s, 1 406 [[1-(1-phenylethyl)-4- H), 7.33(s, 1 H), 7.27-7.22 (m, 6 H), 6.12 (d, piperidyl]methyl]-1H- J = 2.4 Hz,1 H), 3.48 (s, 3 H), 3.27-3.25 (m, pyrrolo[2,3-c]pyridine-4- 2 H), 2.86(s, 3 H), 2.65-2.63 (m, 1 H), carboxamide 2.50-2.47 (m, 4 H), 1.83-1.80(m, 3 H), 1.77-1.56 (m, 2 H), 1.22-1.20 (m, 3 H) 198 N-[[1-[(2- ¹H NMR(400 MHz, DMSO-d6): δ 12.13 (s, 1 427 chlorophenyl)methyl]-4- H),7.44-7.39 (m, 3 H), 7.32-7.24 (m, 3 H), piperidyl]methyl]-N,6- 6.18 (d,J = 2.4 Hz, 1 H), 3.53 (s, 5 H), dimethyl-7-oxo-1H- 2.94 (s, 3 H),2.78-2.75 (m, 2 H), 2.50-2.47 (m, 2 pyrrolo[2,3-c]pyridine-4- H),2.02-1.98 (m, 2 H), 1.70-1.57 (m, 3 H), carboxamide 1.24-1.20 (m, 2 H).199 N-[[1-[(3- ¹H NMR (400 MHz, CD₃OD): δ 427 chlorophenyl)methyl]-4-7.40-7.29 (m, 6 H), 6.34 (d, J = 2.4 Hz, 1 H), 3.67 (s, 3piperidyl]methyl]-N,6- H), 3.52-3.42 (m, 4 H), 3.08 (s, 3 H),dimethyl-7-oxo-1H- 2.90-2.86 (m, 2 H), 2.04-1.98 (m, 2 H),pyrrolo[2,3-c]pyridine-4- 1.77-1.63 (m, 5 H). carboxamide 200 N-[[1-[(4-¹H NMR (400 MHz, DMSO-d6): δ 12.08 (s, 1 427 chloropbenyl)methyl]-4- H),7.34-7.25 (m, 6 H), 6.12 (s, 1 H), 3.48 (s, piperidyl]methyl]-N,6- 3 H),3.36-3.31 (m, 2 H), 2.89 (s, 3 H), dimethyl-7-oxo-1H- 2.70-2.68 (m, 2H), 2.50-2.47 (m, 2 H), pyrrolo[2,3-c]pyridine-4- 1.86-1.84 (m, 2 H),1.63-1.51 (m, 3 H), 1.13-1.10 (m, 2 carboxamide H). 201 N-[[1-[(2- ¹HNMR (400 MHz, DMSO-d6): δ 12.12 (s, 1 411 fluorophenyl)methyl]-4- H),7.38-7.28 (m, 4 H), 7.17-7.11 (m, 2 H), piperidyl]methyl]-N,6- 6.17 (s,1 H), 3.52-3.48 (m, 5 H), 2.93 (s, 3 dimethyl-7-oxo-1H- H), 2.75-2.71(m, 2 H), 2.50-2.47 (m, 2 H), pyrrolo[2,3-c]pyridine-4- 1.97-1.92 (m, 2H), 1.66-1.56 (m, 3 H), carboxamide 1.10-1.08 (m, 2 H). 202 N-[[1-[(3-¹H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 411 fluorophenyl)methyl]-4- H),7.39-7.31 (m, 3 H), 7.12-7.07 (m, 3 H), piperidyl]methyl]-N,6- 6.17 (s,1 H), 3.52 (s, 3 H), 3.44 (s, 2 H), dimethyl-7-oxo-1H- 2.93 (s, 3 H),2.76-2.71 (m, 2 H), 2.50-2.47 (m, 2 pyrrolo[2,3-c]pyridine-4- H),1.91-1.89 (m, 2 H), 1.68-1.56 (m, 3 H), carboxamide 1.18-1.15 (m, 2 H).203 N-[[1-[(4- ¹H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 411fluorophenyl)methyl]-4- H), 7.38-7.29 (m, 4 H), 7.13-7.09 (m, 2 H),piperidyl]methyl]-N,6- 6.17 (s, 1 H), 3.52 (s, 3 H), 3.40 (s, 2H),dimethyl-7-oxo-1H- 2.93 (s, 3 H), 2.74-2.71 (m, 2 H), 2.50-2.47 (m, 2pyrrolo[2,3-c]pyridine-4- H), 1.88-1.82 (m, 2 H), 1.66-1.57 (m, 3 H),carboxamide 1.15-1.08 (m, 2 H). 204 N,6-dimethyl-N-[[1-(m- ¹H NMR (400MHz, CD₃OD): δ 12.13 (s, 1 406 tolylmethyl)-4- H), 7.38 (s, 1 H), 7.32(s, 1 H), 7.19-7.15 (m, piperidyl]methyl]-7-oxo- 1 H), 7.06-7.02 (m, 3H), 6.17 (s, 1 H), 1H-pyrrolo[2,3- 3.52 (s, 3 H), 3.36 (s, 2 H), 2.93(s, 3 H), c]pyridine-4- 2.74-2.71 (m, 2 H), 2.27 (s, 3 H), 1.88-1.85 (m,2 H), carboxamide 1.67-1.55 (m, 3 H), 1.15-1.08 (m, 2 H). 205N-[(1-cyclopentyl-4- ¹H NMR (400 MHz, CD₃OD): δ 7.40 (s, 2 H), 371piperidyl)methyl]-N,6- 6.35 (d, J = 3.2 Hz, 1 H), 3.67 (s, 3 H),dimethyl-7-oxo-1H- 3.49-3.45 (m, 2 H), 3.09-2.93 (m, 5 H),pyrrolo[2,3-c]pyridine-4- 2.55-2.52 (m, 1 H), 1.91-1.40 (m, 15 H).carboxamide 206 N-[[1- ¹H NMR (400 MHz, CD₃OD): δ 7.43 (s, 1 H), 399(cyclohexylmethyl)-4- 7.42 (s, 1 H), 6.36 (s, 1 H), 3.68 (s, 3 H),piperidyl]methyl]-N,6- 3.50-3.45 (m, 4 H), 3.11 (s, 3 H),dimethyl-7-oxo-1H- 2.90-2.85 (m, 4 H), 2.12-1.71 (m, 10 H), 1.37-1.22(m, pyrrolo[2,3-c]pyridine-4- 4 H), 1.10-1.06 (m, 2 H). carboxamide

Example 207N-(1-isobutyl-4-piperidyl)-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:N,6-dimethyl-7-oxo-N-(4-piperidyl)-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride

To a 40 mL vial was added6-methyl-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylicacid (Intermediate E, 1.24 g, 2.6 mmol) N,N-dimethylformamide (10 mL),HATU (1.1 g, 2.9 mmol), and triethylamine (1.09 mL 7.8 mmol). Thereaction was stirred for 15 minutes. Tert-butyl4-(methylamino)piperidine-1-carboxylate (1.5 equiv., 3.9 mmol) was thenadded, and the reaction was shaken at room temperature for 4 h. Thereaction was then diluted with ethyl acetate, and then washed withwater. The aqueous solution was further extracted 2 times with ethylacetate. The combined organic extracts were dried over sodium sulfate,and concentrated under reduced pressure to affort 1.09 g of crudeproduct. The crude material was up in methanol (20 mL) and 4N hydrogenchloride in dioxane (20 mL). The reaction was stirred at roomtemperature for 1 h and then concentrated under reduced pressure toyield 965 mg of product that was 80% pure by LCMS. LCMS M/Z (M+H) 443.This material was used without further purification.

Step 2:N-(1-isobutyl-4-piperidyl)-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

MP-Cyanoborobydride (0.2 g, 2.39 mmol/g, 0.48 mmol) was added to amixture ofN,6-dimethyl-7-oxo-N-(4-piperidyl)-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride (75 mg, 0.16 mmol), methanol (0.75 mL), 1,2-dichloroethane(0.75 mL), isobutyraldehyde (23 mg, 0.32 mmol) and triethylamine (0.043mL, 0.31 mmol). The reaction was shaken at room temperature overnightand the mixture was filtered, washing the resin with methanol. Thefiltrate was concentrated under reduced pressure and the residue waspurified by preperative HPLC (5-85% MeOH/0.1% NH4OH in H2O) to giveN-(1-isobutyl-4-piperidyl)-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(11.2 mg, 20%). ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 2H), 7.39-7.29 (m,3H), 6.18 (d, J=2.8 Hz, 2H), 3.72-3.67 (m, 1H), 3.52 (s, 5H), 2.91-2.78(m, 2H), 2.28-2.23 (m, 3H), 2.05-1.95 (m, 3H), 1.84-1.65 (m, 4H),1.63-1.56 (m, 2H), 0.88-0.80 (m, 6H). LCMS M/Z (M+H) 345.

The following compounds were prepared in a similar fashion to Example207. Examples 208-209

Example Compound Name NMR m/z 208 N-[1- ¹H NMR (400 MHz, DMSO-d₆) δ12.12 (s, 1H), 343 (cyclopropylmethyl)- 7.39-7.29 (m, 2H), 6.19 (d, J =2.7 Hz, 1H), 4-piperidyl]-N,6- 3.52 (s, 3H), 3.30 (s, 31H), 3.03-2.98(m, 2H), 2.83 (s, dimethyl-7-oxo-1H- 3H), 2.29-2.24 (m, 2H), 1.86-1.81(m, 2H), pyrrolo[2,3- 1.81-1.73 (m, 1H), 1.60 (d, J = 10.8 Hz, 2H),c]pyridine-4- 0.80 (d, J = 8.1 Hz, 1H), 0.49-0.39 (m, 2H), carboxamide0.13-0.02 (m, 2H). 209 Trans-N-(3-fluoro-1- ¹H NMR (400 MHz, DMSO-d₆) δ12.07 (s, 1H), 335 isopropyl-4- 8.02 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H),piperidyl)-6-methyl- 7.37-7.26 (m, 1H), 6.69 (dd, J = 2.8, 1.6 Hz, 1H),4.52 (dtd, J = 50.3, 7-oxo-1H- 9.6, 5.0 Hz, 1H), 3.91 (d, J = 7.1 Hz,1H), pyrrolo[2,3- 3.56 (s, 3H), 3.21-3.06 (m, 1H), 2.94-2.60 (m,c]pyridine-4- 2H), 2.29-2.08 (m, 2H), 1.89 (d, J = 14.6 Hz, carboxamide1H), 1.50 (tt, J = 12.5, 6.1 Hz, 1H), 0.98 (dd, J = 6.6, 3.3 Hz, 6H).

Example 210N-(1,4-dimethyl-4-piperidyl)-6-methyl-7-ox-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: tert-butyl4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate

A mixture of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylicacid (Intermediate C, 5.0 g, 20.5 mmol), triethylamine (4.3 mL, 30.8mmol) and diphenylphosphoryl azide (6.0 mL, 29.8 mmol) in toluene (100mL) was stirred at room temperature for 1 h. Benzyl alcohol (5.4 mL,51.3 mmol) was added into the reaction mixture and the reaction mixturewas heated at 80° C. for 18 h, at which time TLC showed the completionof the reaction. The solvent was evaporated and the residue wasdissolved in ethyl acetate (100 mL). The solution was washed with water(30 mL×2), dried over sodium sulfate and concentrated under reducedpressure. The crude product was purified by silica gel chromatography(petroleum ether: ethyl acetate=3:1) to give the title compound (1.8 g,25.2% yield) as colorless oil. LCMS M/Z (M+H) 349.1.

Step 2: benzyl (4-methylpiperidin-4-yl)carbamate hydrochloride

tert-Butyl4-(((benzyloxy)carbonyl)amino)-4-methylpiperidine-1-carboxylate (1.3 g,3.73 mmol) in dioxane (30 mL) was treated with hydrogen chloride (4 N indioxane, 10 mL). The reaction mixture was stirred at room temperaturefor 2 h, at which time TLC indicated that the reaction had gone tocompletion. The mixture was concentrated under reduced pressure to givethe crude title compound (1.0 g, 100% yield) as colorless oil. Thismaterial was used into next step without further treatment. LCMS M/Z(M+H) 248.9.

Step 3: benzyl (1,4-dimethylpiperidin-4-yl)carbamate

A mixture of benzyl (4-methylpiperidin-4-yl)carbamate hydrochloride (650mg, 2.3 mmol), formaldehyde (aq. 35-40%, 1 mL) and sodiumcyanoborohydride (289 mg, 4.6 mmol) in methanol (30 mL) was stirred at90° C. for 3 h, at which time LCMS indicated the reaction had gone tocompletion. The reaction was quenched by addition of saturated aqueousammonium chloride (5 mL). This mixture was adjusted to pH 8-9 usingsaturated aqueous sodium bicarbonate and the resulting mixture wasextracted with ethyl acetate (3×30 mL). The combined organic extractswere dried over sodium sulfate and concentrated under reduced pressureto give the crude title compound (300 mg, 49.7% yield) as colorless oil.LCMS M/Z (M+H) 263.1.

Step 4: 1,4-dimethylpiperidin-4-amine di-hydrochloride

A mixture of benzyl (1,4-dimethylpiperidin-4-yl)carbamate (300 mg, 1.16mmol) and palladium on charcoal (50 mg) in methanol (50 mL) andconcentrated hydrochloric acid (one drop) was stirred under a hydrogenatmosphere (balloon) for 18 h, at which time LCMS indicated the reactionhad gone to completion. The mixture was filtered through a short pad ofCelite and rinsed with methanol (10 mL). The combined organic filtrateswere concentrated under reduced pressure to give the crude titlecompound (100 mg, 43% yield) as light yellow oil. This crude materialwas used directly in the next step.

Step 5N-(1,4-dimethyl-4-piperidyl)-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

HATU (305 mg, 0.80 mmol) was added to a mixture of6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (IntermediateC) (141 mg, 0.73 mmol), 1,4-dimethylpiperidin-4-amine di-hydrochloride(189 mg, 1.47 mmol), and diisopropylethylamine (300 mg, 2.32 mmol) inDMF (2 mL). The resulting mixture was stirred at room temperature for 2h, at which time LCMS indicated that the reaction had gone tocompletion. The mixture was diluted with water (10 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic extracts were driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by preparative HPLC, acetonitrile: water (10 nM ammoniabicarbonate), 0%-30%, to give the title compound (49 mg, 22.3% yield) asa white solid. ¹H NMR (400 MHz, CD₃OD): δ 7.68 (s, 1H), 7.37 (d, J=2.8Hz, 1H), 6.68 (d, J=2.8 Hz, 1H), 3.67 (s, 3H), 2.69-2.60 (m, 2H),2.46-2.32 (m, 7H), 1.8-1.65 (m, 2H), 1.48 (s, 3H). LCMS M/Z (M+H) 303.1.

Example 211N-[(1,4-dimethyl-4-piperidyl)methyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: tert-butyl 4-cyano-4-methylpiperidine-1-carboxylate

Under nitrogen protection, LDA (IM in THF, 26.2 mL, 26.2 mmol) was addeddropwise to a stirred and cooled (−78° C.) solution of tert-butyl4-cyanopiperidine-1-carboxylate (5.0 g, 23.8 mmol) in THF (100 mL).After addition, the reaction mixture was stirred at −78° C. for 1 h, andthen methyl iodide (1.48 mL, 23.8 mmol) was added dropwise. Theresulting mixture was allowed warm to room temperature and stirring wascontinued for 2 h. The reaction was quenched by addition of saturatedaqueous ammonium chloride (50 mL), and extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with brine, driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (petroleum ether: ethylacetate 4:1) to give the title compound (4.3 g, 81% yield) as lightyellow oil. ¹H NMR (400 MHz, CDCl₃): δ 4.10-3.95 (m, 2H), 3.10-2.95 (m,2H), 1.90-1.85 (d, J=12 Hz, 2H), 1.45-1.32 (m, 14H).

Step 2: tert-butyl 4-(aminomethyl)-4-methylpiperidine-1-carboxylate

Raney-Ni (3.0 g) was carefully added to a solution of tert-butyl4-cyano-4-methylpiperidine-1-carboxylate (4.3 g, 19.2 mmol) in methanolunder nitrogen. After addition, the mixture was stirred under hydrogen(50 psi) for 2 h at room temperature. The resulting mixture was filteredthrough a short pad of Celite using dichloromethane to rinse. Thefiltrate was concentrated under reduced pressure to give the titlecompound (4.0 g, 91.5% yield) as light brown oil. This crude materialwas used directly in the next step. LCMS M/Z (M+H) 229.1.

Step 3: tert-butyl4-methyl-4-[[(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]methyl]piperidine-1-carboxylate

HATU (294 mg, 0.8 mmol) was added to the mixture of6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid(Intermediate C) (135 mg, 0.7 mmol), tert-butyl4-(aminomethyl)-4-methylpiperidine-1-carboxylate (160 mg, 0.7 mmol), anddiisopropylethylamine (181 mg, 1.4 mmol) in DMF (3 mL). After addition,the reaction mixture was stirred at room temperature for 2 h, at whichtime LCMS indicated that the reaction had gone to completion. Themixture was quenched by addition of water (5 mL) and extracted withethyl acetate (2×10 mL). The combined organic extracts were washed withbrine, dried over sodium sulfate and concentrated under reduced pressureto give the crude title compound (275 mg, 94% yield) as light brown oil.This crude material was used directly in the next step. LCMS M/Z (M+H)402.9.

Step 4:N-((1,4-dimethylpiperidin-4-yl)methyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

tert-Butyl4-methyl-4-[[(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)amino]methyl]piperidine-1-carboxylate(275 mg, 0.7 mmol) was treated with 4N hydrogen chloride in ethylacetate (10 mL) for 1 h at room temperature. The mixture wasconcentrated under reduced pressure and the residue was mixed withparaformaldehyde (18 mg, 0.6 mmol), triethylamine (90 mg, 0.9 mmol), andmethanol (5 mL). The resulting mixture was heated at 90° C. for 2 h andthen cooled to 0° C. Sodium borohydride (45 mg, 1.2 mmol) was added tothe mixture in one portion and stirring was continued for 30 min at roomtemperature, at which time LCMS indicated the reaction had gone tocompletion. The mixture was concentrated under reduced pressure and theresidue was purified by preparative HPLC (acetonitrile: water (0.3%formic acid), 1%-30%) to give the title compound (30.1 mg, 32.3%) as awhite solid. ¹H NMR (400 MHz, CD₃OD): δ 7.78 (s, 1H), 7.38 (d, J=2.8 Hz,1H), 6.73 (d, J=2.8 Hz, 1H), 3.67 (s, 3H), 3.49-3.20 (m, 6H), 2.87 (s,3H), 1.83-1.81 (m, 2H), 1.68-1.65 (m, 2H), 1.13 (s, 3H). LCMS M/Z (M+H)317.2.

The following compound was prepared in a similar fashion to Example 211.Examples 212

Example Compound Name NMR m/z 212 N-[(1-isopropyl-4- ¹H NMR (400 MHz,CD₃OD): δ 8.34 (s, 1 H), 345 methyl-4- 7.76 (s, 1 H), 7.38 (d, J = 2.8Hz, 1 H), 6.73 (d, piperidyl)methyl]-6- J = 2.4 Hz, 1 H), 3.67 (s, 3 H),3.50-3.10 (m, 7 methyl-7-oxo-1H- H), 1.86-1.83 (m, 2 H), 1.71-1.67 (m, 2H), pyrrolo[2,3-c]pyridine- 1.37 (d, J = 8.0 Hz, 6 H), 1.12 (s, 3H).4-carboxamide

Example 213N-[1-[(4-cyanophenyl)methyl]-4-piperidyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1:N,6-dimethyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride

To a 40 mL vial was added6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (IntermediateC, 690 mg. 3.6 mmol) followed by N,N-dimethylformamide (10 mL), HATU(1.67 g, 4.4 mmol), triethylamine (2.02 mL, 14.5 mmol) and tert-butyl4-(methylamino)piperidine-1-carboxylate (900 mg., 4.2 mmol). Thereaction was capped and shaken at room temperature for 2 h. Theresulting precipitate was collected by filtration, washed with ethylacetate, and dried to afford the desired boc-protected amineintermediate (513 mg, 36%). This material was suspended in methanol (4mL) and hydrogen chloride (4 N in dioxane, 4 mL) was added. The reactionwas shaken at room temperature for 1 h and then concentrated underreduced pressure to affordN,6-dimethyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride (425 mg, 36%). This material was used directly in the nextstep.

Step 2:N-[1-[(4-cyanophenyl)methyl]-4-piperidyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a 4 mL vial was addedN,6-dimethyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride (43 mg, 0.13 mmol) followed by N,N-dimethylformamide (0.5mL), diisopropylethylamine (3 equiv., 0.40 mmol), and4-(bromomethyl)benzonitrile (1.1 equiv., 0.15 mmol). The reaction wascapped and shaken at 50° C. overnight. After cooling, the mixture wasdiluted with dichloromethane, washed with water and concentrated underreduced pressure. The residue was purified by preparative HPLC (5-85%MeOH/0.1% NH4OH in H2O) to yieldN-[1-[(4-cyanophenyl)methyl]-4-piperidyl]-N,6-dimethyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(25 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.82-7.74 (m,2H), 7.50 (dd, J=8.2, 3.4 Hz, 2H), 7.39-7.28 (m, 2H), 6.18 (d, J=2.8 Hz,1H), 4.01 (s, 1H), 3.53 (d, J=5.4 Hz, 5H), 2.83 (s, 5H), 1.99 (d, J=15.0Hz, 2H), 1.89-1.70 (m, 2H), 1.61 (d, J=11.5 Hz, 2H). LCMS M/Z (M+H) 404.

The following compounds were prepared in a similar fashion to Example213. Examples 214-243

Example Compound Name NMR m/z 214 N,6-dimethyl-7-oxo-N-[1- ¹H NMR (400MHz, DMSO-d₆) δ 393 (1-phenylethyl)-4- 7.41-7.12 (m, 7H), 6.16 (d, J =2.7 Hz, 1H), 3.51 (s, piperidyl]-1H- 3H), 3.48-3.37 (m, 1H), 3.09-2.59(m, pyrrolo[2,3-c]pyridine-4- 4H), 1.94-1.59 (m, 6H), 1.33-1.23 (m,carboxamide 3H). 215 N-[1-[(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 404cyanophenyl)methyl]-4- 1H), 7.80 (ddd, J = 8.0, 4.0, 1.3 Hz, 1H),piperidyl]-N,6-dimethyl- 7.72-7.62 (m, 1H), 7.60-7.52 (m, 1H),7-oxo-1H-pyrrolo[2,3- 7.51-7.41 (m, 1H), 7.39-7.29 (m, 2H), 6.19 (d, J =2.7 Hz, c]pyridine-4-carboxamide 1H), 3.61 (d, J = 5.8 Hz, 2H), 3.52 (s,3H), 2.82 (s, 5H), 2.12-2.01 (m, 2H), 1.86-1.72 (m, 2H), 1.66-1.58 (m,2H). 216 N-[1-[(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 397fluorophenyl)methyl]-4- 1H), 7,44-7.25 (m, 4H), 7.21-7.09 (m,piperidyl]-N,6-dimethyl- 2H), 6.18 (d, J = 2.7 Hz, 1H), 3.99 (s, 1H),7-oxo-1H-pyrrolo[2,3- 3.54-3.44 (m, 5H), 2.92-2.80 (m, 5H),c]pyridine-4-carboxamide 2.01-1.93 (m, 3H), 1.87-1.69 (m, 3H), 1.65-1.56(m, 2H). 217 N-(1-isopentyl-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 359piperidyl)-N,6-dimethyl- 1H), 7.38-7.28 (m, 2H), 6.18 (t, J = 2.1 Hz,7-oxo-1H-pyrrolo[2,3- 1H), 3.96 (s, 1H), 3.52 (s, 3H), 3.30 (d, J = 18.3Hz, c]pyridine-4-carboxamide 1H), 2.89 (d, J = 8.6 Hz, 2H), 2.82 (s,3H), 2.27-2.19 (m, 2H), 1.82-1.69 (m, 5H), 1.63-1.47 (m, 3H), 1.28 (q, J= 7.2 Hz, 2H), 0.85 (d, J = 6.6 Hz, 6H). 218 N,6-dimethyl-7-oxo-N-[1- ¹HNMR (400 MHz, DMSO-d₆) δ 12.11 (s, 393 (p-tolylmethyl)-4- 1H), 7.33 (d,J = 18.8 Hz, 2H), piperidyl]-1H- 7.19-7.07 (m, 4H), 6.18 (d, J = 2.7 Hz,1H), 3.99 (s, pyrrolo[2,3-c]pyridine-4- 1H), 3.52 (s, 3H), 3.40-3.23 (m,5H), carboxamide 2.88-2.80 (m, 5H), 2.27 (s, 3H), 1.91-1.86 (m, 2H),1.85-1.71 (m, 2H), 1.63-1.55 (m, 2H). 219 N-[1- ¹H NMR (400 MHz,DMSO-d₆) δ 12.11 (s, 371 (cyclopentylmethyl)-4- 1H), 7.38-7.28 (m, 2H),6.21-6.15 (m, piperidyl]-N,6-dimethyl- 1H), 3.96 (s, 1H), 3.52 (s, 3H),2.91 (d, J = 8.9 Hz, 7-oxo-1H-pyrrolo[2,3- 2H), 2.82 (s, 3H), 2.17-2.10(m, c]pyridine-4-carboxamide 2H), 2.08-1.95 (m, 1H), 1.83-1.72 (m, 5H),1.69-1.41 (m, 9H), 1.21-1.08 (m, 2H). 220 N-[1-[(3- ¹H NMR (400 MHz,DMSO-d₆) δ 12.11 (s, 404 cyanophenyl)methyl]-4- 1H), 7.75-7.68 (m, 2H),7.64 (d, J = 7.9 Hz, piperidyl]-N,6-dimethyl- 1H), 7.54 (t, J = 7.9 Hz,1H), 7.39-7.28 (m, 7-oxo-1H-pyrrolo[2,3- 2H), 6.18 (d, J = 2.7 Hz, 1H),4.01 (s, 1H), c]pyridine-4-carboxamide 3.51 (d, J = 6.5 Hz, 5H), 2.84(s, 5H), 2.72 (d, J = 10.8 Hz, 0H), 1.99-1.94 (m, 2H), 1.88-1.75 (m,2H), 1.65-1.57 (m, 2H). 221 N-[1-[(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11(s, 409 methoxyphenyl)methyl]- 1H), 7.38-7.28 (m, 2H), 7.21-7.14 (m,4-piperidyl]-N,6- 2H), 6.91-6.83 (m, 2H), 6.18 (d, J = 2.7 Hz,dimethyl-7-oxo-1H- 1H), 3.98 (s, 1H), 3.73 (s, 3H), 3.52 (s, 3H),pyrrolo[2,3-c]pyridine-4- 3.35 (s, 2H), 2.82 (s, 5H), 1.87 (s, 2H),carboxamide 1.84-1.70 (m, 2H), 1.63-1.55 (m, 2H). 222 N-[1-[(3- ¹H NMR(400 MHz, DMSO-d₆) δ 12.11 (s, 409 methoxyphenyl)methyl]- 1H), 7.39-7.28(m, 2H), 7.22 (t, J = 7.8 Hz, 4-piperidyl]-N,6- 1H), 6.89-6.76 (m, 3H),6.18 (d, J = 2.8 Hz, dimethyl-7-oxo-1H- 1H), 4.00 (s, 1H), 3.73 (s, 3H),3.52 (s, 3H), pyrrolo[2,3-c]pyridine-4- 3.40 (s, 2H), 2.83 (s, 5H),1.94-1.89 (m, carboxamide 2H), 1.87-1.73 (m, 2H), 1.64-1.56 (m, 2H). 223N-[1-[(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 413chlorophenyl)methyl]-4- 1H), 7.52-7.43 (m, 1H), 7.45-7.23 (m,piperidyl]-N,6-dimethyl- 5H), 6.19 (d, J = 2.8 Hz, 1H), 4.07 (s, 1H),7-oxo-1H-pyrrolo[2,3- 3.56-3.50 (m, 5H), 2.92-2.81 (m, 5H),c]pyridine-4-carboxamide 2.06-2.01 (m, 2H), 1.88-1.74 (m, 2H), 1.66-1.58(m, 2H). 224 N-[1-[(3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 413chlorophenyl)methyl]-4- 1H), 7.39-7.21 (m, 8H), 6.18 (d, J = 2.8 Hz,piperidyl]-N,6-dimethyl- 1H), 4.00 (s, 1H), 3.52 (s, 3H), 3.44 (s, 3H),7-oxo-1H-pyrrolo[2,3- 2.86-2.81 (m, 5H), 2.02-1.91 (m, 3H),c]pyridine-4-carboxamide 1.88-1.70 (m, 3H), 1.65-1.57 (m, 2H). 225N-[1-(2-methoxyethyl)-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 347piperidyl]-N,6-dimethyl- 1H), 7.38-7.28 (m, 2H), 6.18 (dd, J = 2.7,7-oxo-1H-pyrrolo[2,3- 1.4 Hz, 1H), 3.96 (s, 1H), 3.52 (s, 3H),c]pyridine-4-carboxamide 3.39 (t, J = 5.8 Hz, 2H), 3.21 (s, 3H), 2.91(d, J = 10.9 Hz, 2H), 2.82 (s, 3H), 2.53 (s, 1H), 2.43 (t, J = 5.9 Hz,2H), 1.95-1.90 (m, 2H), 1.84-1.70 (m, 2H), 1.62-1.54 (m, 2H). 226N-[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 357 cyclopropylethyl)-4-1H), 7.39-7.28 (m, 2H), 6.19 (t, J = 2.3 Hz, piperidyl]-N,6-dimethyl-1H), 3.99 (s, 1H), 3.52 (s, 3H), 7-oxo-1H-pyrrolo[2,3- 2.96-2.91 (m,2H), 2.82 (s, 4H), 2.35 (s, 2H), c]pyridine-4-carboxamide 1.90-1.85 (m,2H), 1.83-1.75 (m, 2H), 1.65-1.60 (m, 2H), 1.36-1.26 (m, 2H), 0.70-0.57(m, 1H), 0.42-0.31 (m, 2H), 0.01 (d, J = 5.9 Hz, 2H). 227N-ethyl-N-(1-isopropyl-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 345piperidyl)-6-methyl-7- 1H), 7.31 (d, J = 6.1 Hz, 2H), 6.15 (d, J = 2.8Hz, oxo-1H-pyrrolo[2,3- 1H), 3.69 (s, 1H), 3.52 (s, 3H),c]pyridine-4-carboxamide 3.38-3.25 (m, 2H), 2.77 (d, J = 10.8 Hz, 2H),2.63 (p, J = 6.6 Hz, 1H), 2.48 (s, 1H), 1.91 (s, 2H), 1.80-1.59 (m, 4H),1.09 (t, J = 6.9 Hz, 3H), 0.89 (d, J = 6.5 Hz, 6H). 228N-(3-isopropyl-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 315azabicyclo[3.1.0]hexan-6- 1H), 7.93 (d, J = 4.2 Hz, 1H), 7.76 (s, 1H),yl)-6-methyl-7-oxo-1H- 7.33-7.27 (m, 1H), 6.72-6.66 (m, 1H),pyrrolo[2,3-c]pyridine-4- 3.53 (s, 3H), 3.06 (d, J = 8.7 Hz, 2H), 2.95(d, J = 3.8 Hz, carboxamide 1H), 2.42-2.32 (m, 3H), 1.57 (s, 2H), 0.98(d, J = 6.2 Hz, 6H). 229 N-[[1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s,413 cyclohexylethyl)-4- 1H), 7.39 (s, 1H), 7.32 (t, J = 2.7 Hz, 1H),piperidyl]methyl]-N,6- 6.20-6.14 (m, 1H), 3.53 (s, 3H),dimethyl-7-oxo-1H- 3.32-3.27 (m, 2H), 2.93 (s, 3H), 2.80-2.75 (m, 2H),pyrrolo[2,3-c]pyridine-4- 2.26-2.17 (m, 2H), 1.81-1.76 (m, 2H),carboxamide 1.66-1.61 (m, 5H), 1.59-1.54 (m, 3H), 1.32-1.22 (m, 2H),1.21-1.05 (m, 6H), 0.92-0.81 (m, 2H). 230 N,6-dimethyl-7-oxo-N- ¹H NMR(400 MHz, DMSO-d₆) δ 12.12 (s, 401 [[1-(tetrahydropyran-3- 1H), 7.39 (s,1H), 7.35-7.29 (m, 1H), ylmethyl)-4- 6.17 (t, J = 2.4 Hz, 1H), 3.79-3.66(m, 2H), piperidyl]methyl]-1H- 3.53 (s, 3H), 3.32-3.20 (m, 2H),3.03-2.91 (m, pyrrolo[2,3-c]pyridine-4- 4H), 2.83-2.78 (m, 1H),2.13-1.96 (m, carboxamide 2H), 1.84-1.76 (m, 1H), 1.74-1.66 (m, 5H),1.56-1.39 (m, 4H), 1.14-1.06 (m, 4H). 231 N,6-dimethyl-7-oxo-N- ¹H NMR(400 MHz, DMSO-d₆) δ 12.12 (s, 387 [[1-(tetrahydrofuran-2- 1H), 7.39 (s,1H), 7.32 (t, J = 2.5 Hz, 1H), ylmethyl)-4- 6.17 (dd, J = 2.9, 1.4 Hz,1H), 3.86 (d, J = 9.1 Hz, piperidyl]methyl]-1H- 1H), 3.70 (q, J = 7.3Hz, 1H), 3.53 (s, pyrrolo[2,3-c]pyridine-4- 4H), 3.30 (t, J = 4.9 Hz,2H), 2.93 (s, 3H), carboxamide 2.79 (s, 1H), 2.33-2.27 (m, 2H),1.97-1.81 (m, 3H), 1.81-1.68 (m, 2H), 1.66-1.61 (m, 2H), 1.55-1.50 (m,2H), 1.49-1.35 (m, 2H), 1.07-1.02 (m, 3H). 232 N-[[1-(3-methoxypropyl)-¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 375 4-piperidyl]methyl]-N,6- 1H),7.39 (s, 1H), 7.35-7.29 (m, 1H), dimethyl-7-oxo-1H- 6.17 (d, J = 2.7 Hz,1H), 3.53 (s, 3H), pyrrolo[2,3-c]pyridine-4- 3.32-3.25 (m, 2H), 3.19 (s,3H), 2.93 (s, 3H), carboxamide 2.81-2.74 (m, 2H), 2.29-2.21 (m, 2H),1.86-1.75 (m, 2H), 1.68-1.52 (m, 6H), 1.08-1.03 (m, 3H). 233N-[[1-(cyclobutylmethyl)- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 3714-piperidyl]methyl]-N,6- 1H), 7.38 (s, 1H), 7.35-7.29 (m, 1H),dimethyl-7-oxo-1H- 6.17 (d, J = 2.8 Hz, 1H), 3.53 (s, 3H),pyrrolo[2,3-c]pyridine-4- 3.32-3.25 (m, 2H), 2.93 (s, 3H), 2.71 (s, 2H),carboxamide 2.48-2.38 (m, 1H), 2.26 (d, J = 7.0 Hz, 2H), 1.96 (d, J =9.8 Hz, 2H), 1.87-1.70 (m, 4H), 1.65-1.53 (m, 4H), 1.05-1.00 (m, 3H).234 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 401[[1-(tetrahydropyran-4- 1H), 7.39 (s, 1H), 7.32 (t, J = 2.6 Hz, 1H),ylmethyl)-4- 6.17 (t, J = 2.1 Hz, 1H), 3.79 (d, J = 10.8 Hz,piperidyl]methyl]-1H- 2H), 3.53 (s, 3H), 3.32-3.20 (m, 2H),pyrrolo[2,3-c]pyridine-4- 2.93 (s, 3H), 2.76 (s, 2H), 2.10-2.03 (m, 2H),carboxamide 1.83-1.75 (m, 2H), 1.70-1.65 (m, 2H), 1.59-1.50 (m, 4H),1.13-1.02 (m, 4H). 235 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ12.12 (s, 401 [[1-(tetrahydropyran-2- 1H), 7.39 (s, 1H), 7.35-7.29 (m,1H), ylmethyl)-4- 6.20-6.14 (m, 1H), 3.80 (d, J = 11.2 Hz, 1H),piperidyl]methyl]-1H- 3.53 (s, 3H), 3.38-3.22 (m, 2H), 2.93 (s, 3H),pyrrolo[2,3-c]pyridine-4- 2.82-2.77 (m, 2H), 2.33-2.23 (m, 1H),carboxamide 2.22-2.13 (m, 1H), 1.94-1.84 (m, 2H), 1.75-1.70 (m, 1H),1.66-1.61 (m, 2H), 1.58-1.50 (m, 3H), 1.47-1.33 (m, 4H), 1.10-1.05 (m,3H). 236 N,6-dimethyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 387[[1-(tetrahydrofuran-3- 1H), 7.39 (s, 1H), 7.32 (t, J = 2.7 Hz, 1H),ylmethyl)-4- 6.18 (t, J = 2.2 Hz, 1H), 3.72-3.50 (m, 6H),piperidyl]methyl]-1H- 3.36-3.27 (m, 1H), 2.93 (s, 3H), 2.82 (s,pyrrolo[2,3-c]pyridine-4- 1H), 2.41-2.33 (m, 1H), 2.23-2.16 (m,carboxamide 2H), 1.92-1.79 (m, 4H), 1.68-1.63 (m, 1H), 1.57-1.52 (m,2H), 1.51-1.41 (m, 2H), 1.08-1.03 (m, 3H). 237 N-cyclobutyl-N-(1- 1H NMR(400 MHz, DMSO-d6) δ 12.13 (d, J = 3.6 Hz, 371 isopropyl-4-piperidyl)-6-1H), 7.34-7.25 (m, 2H), 6.14 (t, J = 2.3 Hz, methyl-7-oxo-1H- 1H), 4.13(p, J = 8.8 Hz, 1H), pyrrolo[2,3-c]pyridine-4- 3.52 (s, 3H), 3.32 (s,11H), 2.79 (d, J = 10.9 Hz, carboxamide 2H), 2.67 (p, J = 8.3, 7.4 Hz,1H), 2.52-2.35 (m, 3H), 2.31 (d, J = 12.7 Hz, 2H), 2.11-1.90 (m, 4H),1.52 (ddd, J = 38.7, 21.9, 9.9 Hz, 4H), 0.93 (d, J = 6.5 Hz, 6H). 238Cis-N-(1-isopropyl-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 331methyl-4-piperidyl)-6- 1H), 7.80 (s, 1H), 7.56-7.49 (m, 1H),methyl-7-oxo-1H- 7.31 (d, J = 2.8 Hz, 1H), 6.64 (d, J = 2.8 Hz, 1H),pyrrolo[2,3-c]pyridine-4- 4.01-3.90 (m, 1H), 3.56 (s, 3H), 2.65 (dq, J =12.3, carboxamide 6.2, 5.7 Hz, 2H), 2.38-2.25 (m, 2H), 2.12-1.99 (m,1H), 1.81-1.67 (m, 1H), 1.62-1.51 (m, 1H), 1.00-0.88 (m, 9H). 239Trans-N-(1-isopropyl-3- ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 331methyl-4-piperidyl)-6- 1H), 7.81 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H),methyl-7-oxo-1H- 7.33-7.28 (m, 1H), 6.68 (d, J = 2.7 Hz, 1H),pyrrolo[2,3-c]pyridine-4- 3.56 (s, 3H), 3.47 (dd, J = 13.7, 6.0 Hz, 1H),carboxamide 2.91-2.75 (m, 3H), 2.33-2.22 (m, 1H), 1.99 (t, J = 11.1 Hz,1H), 1.86-1.67 (m, 2H), 1.60-1.46 (m, 1H), 1.01 (d, J = 6.5 Hz, 7H),0.87 (d, J = 6.5 Hz, 3H). 240 Cis-N-(3-fluoro-1- ¹H NMR (400 MHz,DMSO-d₆) δ 12.06 (s, 335 isopropyl-4-piperidyl)-6- 1H), 7.92 (s, 1H),7.84 (d, J = 7.6 Hz, 1H), methyl-7-oxo-1H- 7.34-7.28 (m, 1H), 6.72-6.66(m, 1H), pyrrolo[2,3-c]pyridine-4- 4.77 (d, J = 49.9 Hz, 1H), 4.03-3.86(m, 1H), carboxamide 3.55 (s, 3H), 3.09-2.99 (m, 1H), 2.85-2.67 (m, 2H),2.50-2.42 (m, 1H), 2.25 (t, J = 11.3 Hz, 1H), 1.94-1.79 (m, 1H),1.69-1.60 (m, 1H), 0.97 (dd, J = 6.6, 4.0 Hz, 6H). 241N-(1-isopropylazepan-4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 331yl)-6-methyl-7-oxo-1H- 1H), 7.80 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H),pyrrolo[2,3-c]pyridine-4- 7.34-7.28 (m, 1H), 6.67 (d, J = 2.7 Hz, 1H),carboxamide 4.09 (ddd, J = 13.2, 8.8, 4.6 Hz, 1H), 3.55 (s, 3H), 3.30(d, J = 19.0 Hz, 1H), 2.92-2.77 (m, 1H), 2.68-2.50 (m, 4H), 1.93-1.81(m, 1H), 1.80-1.60 (m, 4H), 1.60-1.47 (m, 1H), 0.94 (dd, J = 6.6, 2.1Hz, 6H). 242 N-(8-isopropyl-8- ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 357azabicyclo[3.2.1]octan-3- 1H), 7.31 (d, J = 2.6 Hz, 2H), 6.17-6.11 (m,yl)-N,6-dimethyl-7-oxo- 1H), 4.48 (s, 1H), 3.52 (s, 3H), 3.47 (d, J =9.1 Hz, 1H-pyrrolo[2,3- 2H), 2.75 (s, 3H), 2.28-2.08 (m,c]pyridine-4-carboxamide 3H), 1.92-1.82 (m, 2H), 1.51-1.41 (m, 2H),1.38-1.27 (m, 2H), 0.90 (d, J = 5.7 Hz, 6H). 243 N-cyclopropyl-N-(1- ¹HNMR (400 MHz, DMSO-d₆) δ 12.02 (s, 357 isopropyl-4-piperidyl)-6- 1H),7.45 (s, 1H), 7.35-7.17 (m, 1H), methyl-7-oxo-1H- 6.32-6.17 (m, 1H),4.01-3.72 (m, 1H), 3.53 (s, pyrrolo[2,3-c]pyridine-4- 3H), 2.95-2.77 (m,2H), 2.77-2.57 (m, carboxamide 2H), 2.22-2.06 (m, 2H), 2.06-1.89 (m,2H), 1.89-1.69 (m, 2H), 0.95 (dd, J = 11.4, 6.6 Hz, 6H), 0.65-0.50 (m,2H), 0.50-0.37 (m, 2H).

Example 2446-methyl-4-(methylamino)piperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid(Intermediate C) (60 mg, 0.3 mmol), triethylamine (90 mg, 0.9 mmol),HATU (200 mg, 0.5 mmol) and tert-butyl N-methyl-N-(4-piperidyl)carbamate(110 mg, 0.5 mmol) in DMF (1 mL) was stirred at 50° C. for 2 h. Thereaction mixture was added to water (10 mL) and extracted with ethylacetate (3×10 mL). The combined organic extracts were dried over sodiumsulfate and concentrated under reduced pressure to yield tert-butylN-methyl-N-[1-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-4-piperidyl]carbamate(100 mg). This intermediate was dissolved in dichloromethane (2 mL) andtrifluoroacetic acid (0.1 mL) was then added. The mixture was stirredfor 1 h at room temperature at which time LCMS indicated that thereaction had gone to completion. The mixture was concentrated underreduced pressure and the residue was purified by SFC chromatography(10-20% CO2/0.1% NH4OH in MeOH) to give the title compound (54 mg, 60%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.33(d, J=2.8 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 3.98 (s, 1H), 3.53 (s, 3H),3.06-2.95 (m, 2H), 2.88 (m, J=15.9 Hz, 2H), 2.36 (s, 3H), 2.07 (s, 1H),1.85 (d, J=12.8 Hz, 2H), 1.25 (d, J 11.3 Hz, 2H). LCMS M/Z (M+H) 289.2.

Example 2456-(2-cyclopropylethyl)-4-(4-(dimethylamino)piperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Step 1 methyl6-(2-cyclopropylethyl)-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-1-carboxylate

Sodium hydride, 60% in mineral oil (35 mg, 0.87 mmol) was added to acooled (0° C.) mixture of methyl7-oxo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridine-4-carboxylate(Intermediate B, 200 mg, 0.58 mmol) in N,N-dimethylformamide (4 mL). Themixture was stirred for 15 min at 0° C. and then2-bromoethylcyclopropane (100 mg, 0.69 mmol) was added. The reaction wasallowed to warm to room temperature and stirring was continued for 18 h.The reaction was diluted with water (20 mL) and then extracted withethyl acetate (3×10 mL). The combined organic extracts were washed withbrine (2×20 mL), dried over sodium sulfate and concentrated underreduced pressure to yield the title compound (200 mg, 100% yield). Thiscrude was used directly in the next step. LCMS M/Z (M+H) 415.4.

Step 26-(2-cyclopropylethyl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylicacid

A mixture of methyl6-(2-cyclopropylethyl)-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-4-carboxylate(200 mg, 0.5 mmol) and lithium hydroxide (50 mg, 2 mmol) indichloromethane (4 mL), methanol (6 mL) and water (1 mL) was stirred at45° C. for 5 h. The mixture was concentrated under reduced pressure andthe residue was dissolved in water (4 mL). The aqueous solution wasacidified to pH 1 with 1N hydrochloric acid. The resulting precipitatewas collected by filtration, washed with water, and dried to yield thetitle compound (100 mg, 80% yield) as a brown solid. LCMS M/Z (M+H)247.2.

Step 36-(2-cyclopropylethyl)-4-(4-(dimethylamino)piperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of6-(2-cyclopropylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid(50 mg, 0.2 mmol), triethylamine (80 mg, 0.8 mmol), HATU (90 mg, 0.3mmol) and N,N-dimethylpiperidin-4-amine (30 mg, 0.3 mmol) inN,N-dimethylformamide (1 mL) was stirred at 50° C. for 1 h. The reactionmixture was added to water (5 mL) and extracted with ethyl acetate (3×10mL). The combined organic extracts were dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified bypreparative HPLC (0-25%/ACN/0.1% NH4OH in H2O) to give6-(2-cyclopropylethyl)-4-(4-(dimethylamino)piperidine-1-carbonyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(22 mg, 30% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.09(s, 1H), 7.41 (s, 1H), 7.33 (d, J=2.8 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H),4.06 (t, J=7.1 Hz, 2H), 3.03-2.80 (m, 2H), 2.30 (dd, J=12.7, 8.9 Hz,1H), 2.16 (s, 6H), 1.75 (d, J=12.3 Hz, 2H), 1.56 (q, J=7.0 Hz, 2H), 1.30(d, J=11.9 Hz, 2H), 0.77-0.58 (m, 1H), 0.44-0.30 (m, 2H). LCMS M/Z (M+H)357.5.

The following compound was prepared in a similar fashion to Example 245.Examples 246-249

Example Compound Name NMR m/z 246 6-but-2-enyl-4-[4- ¹H NMR (400 MHz,DMSO-d6) δ 12.14 (s, 343.2 (dimethylamino)piperidine- 1H), 7.45-7.25 (m,2H), 6.25 (t, J = 2.3 Hz, 1-carbonyl]-1H- 1H), 5.77-5.50 (m, 2H), 4.55(d, J = 5.4 Hz, pyrrolo[2,3-c]pyridin-7- 2H), 2.91 (t, J = 12.5 Hz, 2H),2.32 (d, J = 3.9 Hz, one 1H), 2.17 (s, 6H), 1.75 (dd, J = 13.1, 4.0 Hz,2H), 1.69-1.62 (m, 3H), 1.30 (dd, J = 11.6, 3.9 Hz, 2H). 2476-but-3-enyl-4-[4- ¹H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 343.2(dimethylamino)piperidine- 1H), 7.36 (s, 1H), 7.33 (d, J = 2.7 Hz, 1H),1-carbonyl]-1H- 6.23 (d, J = 2.7 Hz, 1H), 5.93-5.73 (m, 1H),pyrrolo[2,3-c]pyridin-7- 5.07-4.93 (m, 2H), 4.07 (t, J = 7.0 Hz, 2H),one 3.02-2.83 (m, 3H), 2.44 (t, J = 6.9 Hz, 2H), 2.30 (m, 1H), 2.17 (s,6H), 1.75 (d, J = 12.6 Hz, 2H), 1.42-1.22 (m, 2H). 2486-butyl-N-[(1-methyl-4- 1H NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 345piperidyl)methyl]-7-oxo- 7.94 (t, J = 5.7 Hz, 1H), 7.78 (s, 1H), 7.31(d, J = 2.7 Hz, 1H-pyrrolo[2,3- 1H), 6.70 (d, J = 2.7 Hz, 1H),c]pyridine-4-carboxamide 4.08-3.91 (m, 2H), 3.13 (t, J = 6.3 Hz, 2H),2.74 (d, J = 11.5 Hz, 2H), 2.12 (d, J = 5.4 Hz, 3H), 1.89-1.74 (m, 2H),1.74-1.59 (m, 4H), 1.59-1.41 (m, 1H), 1.41-1.27 (m, 2H), 1.27-1.11 (m,2H), 0.98-0.84 (m, 3H).

Example 2496-allyl-N-[(1S,5R)-3-(2-cyanopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: tert-butyl(1R,5S)-6-[(2,4-dinitrophenyl)sulfonylamino]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a flask was added tert-butyl(1R,5S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 2.50mmol) and dichloromethane (50 mL). The solution was cooled to 0° C. and2,6-lutidine (2.9 mL, 25.0 mmol) and 2,4-dinitrobenzenesulfonyl chloride(0.67 g, 2.50 mmol) were then added. The reaction was stirred at 0° C.for 30 minutes, then allowed to warm to room temperature and stirredovernight. The reaction was diluted with water (100 mL). This mixturewas acidified to pH 2.5 using 5% potassium hydrogen sulfate in water.The organic phase was separated, washed with brine, dried over sodiumsulfate, and concentrated under reduced pressure to afford crude titlecompound. This material was used directly in the next step assumingtheoretical yield. LCMS M/Z (M−H) 427.

Step 2:tert-butyl(1R,5S)-6-[(2,4-dinitrophenyl)sulfonyl-methyl-amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate

The crude tert-butyl(1R,5S)-6-[(2,4-dinitrophenyl)sulfonylamino]-3-azabicyclo[3.1.0]hexane-3-carboxylate(107 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (20 mL), andcooled to 0° C. Sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol)was then added and the reaction was stirred at 0° C. for 10 minutes.Iodomethane (0.047 mL, 0.75 mmol) was added. The reaction was allowed towarm to room temperature, and stirred for an additional 4 h. Thereaction was then diluted with dichloromethane (100 mL), and washed withwater. The organic solution was concentrated under reduced pressure andthe residue was purified by silica gel chromatography (0-5%methanol:dichloromethane) yielding title compound (715 mg, 65% for 2steps). ¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=2.3 Hz, 1H), 8.61 (dd,J=8.7, 2.3 Hz, 1H), 8.29 (d, J=8.7 Hz, 1H), 3.49 (d, J=11.0 Hz, 2H),3.35-3.27 (m, 4H), 2.90 (s, 3H), 2.10-2.01 (m, 3H), 1.35 (s, 9H).

Step 3: tert-butyl(1R,5S)-6-[(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-methyl-amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a 40 mL vial was added tert-butyl(1R,5S)-6-[(2,4-dinitrophenyl)sulfonyl-methyl-amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate(650 mg, 1.47 mmol), dichloromethane (10 mL), and propan-1-amine (0.36mL, 4.41 mmol). The reaction was stirred at room temperature for 4 h atwhich point LCMS showed loss of starting material. The reaction wasconcentrated under reduced pressure. This crude was carried on withoutpurification.

To a 20 mL vial was added6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (Example 159,step 1, 200 mg, 0.92 mmol), N,N-dimethylformamide (4 mL), HATU (365 mg,0.96 mmol), and triethylamine (0.51 mL, 3.66 mmol). The reaction wascapped and shaken at room temperature for 15 minutes. tert-Butyl(1R,5S)-6-(methylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.3equiv., 1.19 mmol) was then added, and the reaction was shaken for 1 h.The reaction was then diluted water (100 mL) and extracted with ethylacetate (3×50 mL). The combined organic extracts were dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (2-5% methanol:dichloromethane),yielding title compound (127 mg, 34%). LCMS M/Z (M+H) Minor: 413, Major:357 (loss of t-butyl fragment).

Step 4:6-allyl-N-[(1R,5S)-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-ox-1H-pyrrolo[2,3-c]pyridine-4-carboxamide;2,2,2-trifluoroacetic acid

To a 4 mL vial was added tert-butyl(1R,5S)-6-[(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-methyl-amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate(87 mg, 0.21 mmol), dichloromethane (0.5 mL), and trifluoroacetic acid(0.08 mL, 1.04 mmol). The reaction was capped and shaken at roomtemperature for 1 h, then concentrated under reduced pressure. Theresidue was azeotroped with ethanol (3×) and dichloromethane (3×) toafford the desired product, which was taken directly to the next step.LCMS M/Z (M+H) 313.

Step 5:6-allyl-N-[(1S,5R)-3-(2-cyanopyrimidin-4-yl-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a 4 mL vial was added 6-allyl-N-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide;2,2,2-trifluoroacetic acid (40 mg, 0.094 mmol), acetonitrile (0.25 mL),diisopropylethylamine (0.049 mL, 0.28 mmol), and4-chloropyrimidine-2-carbonitrile (14 mg, 0.10 mmol). The reaction wascapped and shaken at 75° C. for 1 h. The reaction was concentrated underreduced pressure and the residue was purified by preparative HPLC (0-25%ACN/0.1% NH4OH in H2O) yielding 6-allyl-N-[(1S,5R)-3-(2-cyanopyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(35 mg, 89%). ¹H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.22 (d, J=6.4Hz, 1H), 7.46 (s, 1H), 7.33 (t, J=2.7 Hz, 1H), 6.67 (d, J=6.4 Hz, 1H),6.34-6.28 (m, 1H), 6.01 (ddt, J=16.2, 10.7, 5.5 Hz, 1H), 5.20-5.05 (m,2H), 4.69-4.61 (m, 2H), 3.61-3.30 (m, 4H), 3.00 (s, 3H), 2.68 (s, 1H),1.97-1.86 (m, 2H). LCMS M/Z (M+H) 416.

The following compounds were prepared in a similar fashion to Example249: Examples 250-251

Example Compound Name NMR m/z 250 6-allyl-N-methyl-7-oxo-N- 1H NMR (400MHz, DMSO-d6) δ 12.10 (d, J = 3.8 Hz, 459 [(1S,5R)-3-[4- 1H), 8.63 (dd,J = 5.0, 2.7 Hz, 1H), (trifluoromethyl)pyrimidin- 7.45 (d, J = 2.6 Hz,1H), 7.31 (q, J = 2.5 Hz, 2-yl]-3- 1H), 7.00 (dd, J = 4.9, 2.7 Hz, 1H),6.30 (d, J = 3.4 Hz, azabicyclo[3.1.0]hexan-6- 1H), 6.08-5.85 (m, 1H),yl]-1H-pyrrolo[2,3- 5.24-4.95 (m, 2H), 4.64 (d, J = 10.9 Hz, 2H),c]pyridine-4-carboxamide 3.52 (d, J = 10.8 Hz, 2H), 3.44-3.32 (m, 2H),3.01 (d, J = 2.8 Hz, 3H), 2.69 (d, J = 2.7 Hz, 1H), 1.86 (s, 2H). 2516-allyl-N-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 391(3-pyrimidin-4-yl-3- 2H), 8.42 (d, J = 1.1 Hz, 1H), 8.11 (d, J = 6.0 Hz,azabicyclo[3.1.0]hexan-6- 1H), 7.46 (s, 1H), 7.35-7.29 (m, 1H),yl)-1H-pyrrolo[2,3- 6.40-6.28 (m, 2H),, 6.08-5.85 (m, 1H),c]pyridine-4-carboxamide 5.18-5.03 (m, 2H), 4.64 (d, J = 5.6 Hz, 2H),3.31 (s, 4H), 3.01 (s, 3H), 2.69-2.63 (m, 1H), 1.89 (s, 2H).

Example 252N,6-dimethyl-7-oxo-N-(1-phenethyl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a microwave vial was addedN,6-dimethyl-7-oxo-N-(4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamidehydrochloride (Example 210, Step 1, 45 mg, 0.14 mmol), acetonitrile (0.2mL), diisopropylethylamine (0.071 mL, 0.42 mmol), water (0.10 mL), and2-bromoethylbenzene (39 mg, 0.21 mmol). The reaction was sealed andstirred under microwave irradiation for 30 minutes at 150° C. Thereaction was then concentrated under reduced pressure and the residuewas purified by preparative HPLC (5-50% ACN/0.1% NH4OH in H2O) yieldingN,6-dimethyl-7-oxo-N-(1-phenethyl-4-piperidyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(22 mg, 41%).

The following compound was prepared in a similar fashion to Example 252.Examples 253-255

Example Compound Name NMR m/z 253 N-[1-[2-(2- ¹H NMR (400 MHz, DMSO-d₆)δ 12.14 (s, 1H), 411 fluorophenyl)ethyl]-4- 7.40-7.18 (m, 4H), 7.17-7.07(m, 2H), piperidyl]-N,6- 6.22-6.16 (m, 1H), 3.74 (s, 1H), 3.52 (s, 3H),dimethyl-7-oxo-1H- 3.02-2.95 (m, 2H), 2.82 (s, 3H), 2.74 (t, J = 7.7 Hz,pyrrolo[2,3- 2H), 2.46 (d, J = 7.5 Hz, 2H), 1.97-1.92 (m, 2H),c]pyridine-4- 1.85-1.71 (m, 2H), 1.65-1.58 (m, 2H). carboxamide 254N-[1-[2-(4- ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 427chlorophenyl)ethyl]-4- 7.39-7.20 (m, 6H), 6.19 (dd, J = 2.8, 1.6 Hz,piperidyl]-N,6- 1H), 3.99 (s, 1H), 3.52 (s, 3H), 3.01-2.93 (m,dimethyl-7-oxo-1H- 2H), 2.82 (s, 3H), 2.70 (t, J = 7.5 Hz, 2H),pyrrolo[2,3- 1.95-1.90 (m, 2H), 1.84-1.70 (m, 2H), 1.65-1.57 (m,c]pyridine-4- 2H). carboxamide 255 N,6-dimethyl-7-oxo- ¹H NMR (400 MHz,DMSO-d₆) δ 12.13 (s, 1H), 407 N-[1-(2- 7.39-7.12 (m, 7H), 6.18 (dd, J =2.8, 1.3 Hz, phenylpropyl)-4- 1H), 3.96 (s, 1H), 3.52 (s, 3H), 2.96-2.86(m, piperidyl]-1H- 3H), 2.81 (s, 3H), 2.39-2.32 (m, 2H), pyrrolo[2,3-1.94-1.89 (m, 1H), 1.82-1.68 (m, 3H), 1.63-1.54 (m, 2H), c]pyridine-4-1.17 (d, J = 6.8 Hz, 3H). carboxamide

Example 256(R)-6-methyl-7-oxo-N-(1-phenylethyl)-6,7-dihydro-1Hpyrrolo[2,3-c]pyridine-4-carboxamide

A vial was charged with4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one(Intermediate D, 45 mg, 0.118 mmol), palladium acetate (2.65 mg, 0.012mmol), and Xantphos (6.83 mg, 0.012 mmol) before being evacuated andpurged with carbon monoxide (3×). Toluene (2 mL) was added, followed by(R)-1-phenylethanamine (28.6 mg, 0.236 mmol), and triethylamine (82 μl,0.590 mmol), and the reaction mixture was stirred at 90° C. for 2 h.After cooling, the mixture was diluted with ethyl acetate and filteredthrough a pad of Celite. The filtrate was concentrated under reducedpressure and the residue was purified by silica gel chromatography(eluting with hexanes and ethyl acetate) to afford crude intermediate.This material was dissolved in methanol (6 mL) and then potassiumhydroxide (33.1 mg, 0.590 mmol) in water (1 mL) was added. The reactionwas stirred at room temperature 18 h. The reaction was filtered throughCelite, using methanol to rinse and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatography(eluting with hexanes and ethyl acetate) to give the title compound as awhite, amorphous solid (10 mg, 29%) after lyophilization from dioxane.¹H NMR (400 MHz, DMSO-d6) δ 12.02-12.10 (m, 1H), 8.34 (d, J=7.69 Hz,1H), 7.94 (s, 1H), 7.40 (d, J=7.06 Hz, 2H), 7.28-7.36 (m, 3H), 7.23 (d,J=7.27 Hz, 1H), 6.67 (t, J=2.29 Hz, 1H), 5.14 (s, 1H), 3.57 (s, 3H),1.46 (d, J=7.27 Hz, 3H). LCMS M/Z (M+H) 296.

The following compounds were prepared in a similar fashion to Example256: Examples 257-264

Example Compound Name NMR m/z 257 N-benzyl-6-methyl-7- 1H NMR (400 MHz,DMSO-d6) δ 12.10 (br. s., 282 oxo-1H-pyrrolo[2,3- 1H), 8.52 (t, J = 6.02Hz, 1H), 7.91 (s, 1H), c]pyridine-4- 7.34 (s, 1H), 7.30-7.34 (m, 2H),7.20-7.28 (m, 1H), carboxamide 6.70-6.77 (m, 1H), 4.46 (d, J = 6.02 Hz,1H), 3.55 (s, 3H). 258 6-methyl-7-oxo-N-(2- ¹H NMR (400 MHz, DMSO-d6) δ12.08 (br. s., 296 phenylethyl)-1H- 1H), 8.03 (br. s., 1H), 7.79 (s,1H), pyrrolo[2,3-c]pyridine- 7.18-7.34 (m, 4H), 6.66 (t, J = 2.39 Hz,1H), 3.54 (s, 3H), 4-carboxamide 3.43-3.51 (m, 2H), 2.84 (t, J = 7.48Hz, 2H). 259 N-benzyl-6-butyl-7-oxo- ¹H NMR (400 MHz, DMSO-d6) δ 3241H-pyrrolo[2,3- 12.02-12.10 (m, 1H), 8.47-8.58 (m, 1H), 7.88 (s, 1H),c]pyridine-4- 7.31-7.37 (m, 4H), 7.21-7.28 (m, 1H), carboxamide6.73-6.77 (m, 1H), 4.47 (d, J = 6.02 Hz, 2H), 3.93-4.04 (m, 2H),1.62-1.75 (m, 2H), 1.25-1.39 (m, 2H), 0.87-0.96 (m, 3H). 260N-benzyl-6-[(E)-but-2- ¹H NMR (400 MHz, DMSO-d6) δ 322 enyl]-7-oxo-1H-11.98-12.21 (m, 2H), 8.46-8.58 (m, 1H), 7.82 (s, 1H),pyrrolo[2,3-c]pyridine- 7.31-7.38 (m, 5H), 7.20-7.28 (m, 1H),4-carboxamide 6.72-6.77 (m, 1H), 5.63 (s, 2H), 4.64-4.72 (m, 1H),4.52-4.59 (m, 2H), 4.47 (d, J = 5.82 Hz, 2H), 1.75-1.81 (m, 1H), 1.66(d, J = 4.36 Hz, 3H). 261 N-[(4- ¹H NMR (400 MHz, DMSO-d6) δ 12.09 (br.s., 312 methoxyphenyl)methyl]- 1H), 8.42 (t, J = 6.02 Hz, 1H), 7.88 (s,1H), 6-methyl-7-oxo-1H- 7.32 (t, J = 2.80 Hz, 1H), 7.26 (d, J = 8.72 Hz,2H), pyrrolo[2,3-c]pyridine- 6.86-6.92 (m, 2H), 6.73 (t, J = 2.39 Hz,1H), 4-carboxamide 4.38 (d, J = 5.82 Hz, 2H), 3.73 (s, 3H), 3.54 (s,3H). 262 6-methyl-7-oxo-N-(2- ¹H NMR (400 MHz, DMSO-d6) δ 12.10 (br. s.,288 thienylmethyl)-1H- 1H), 8.59 (s, 1H), 7.87 (s, 1H), 7.39 (d, J =4.99 Hz, pyrrolo[2,3-c]pyridine- 1H), 7.33 (t, J = 2.80 Hz, 1H), 7.02(br. s., 4-carboxamide 1H), 6.94-7.00 (m, 1H), 6.74 (s, 1H), 4.61 (d, J= 5.82 Hz, 3H), 3.54 (s, 3H). 263 N-[(4- ¹H NMR (400 MHz, DMSO-d6) δ12.10 (br. s., 300 fluorophenyl)methyl]-6- 1H), 8.52 (t, J = 5.92 Hz,1H), 7.90 (s, 1H), methyl-7-oxo-1H- 7.34-7.42 (m, 2H), 7.33 (t, J = 2.80Hz, 1H), pyrrolo[2,3-c]pyridine- 7.11-7.20 (m, 2H), 6.74 (t, J = 2.49Hz, 1H), 4.44 (d, 4-carboxamide J = 5.82 Hz, 2H), 3.55 (s, 3H). 2646-methyl-7-oxo-N- ¹H NMR (400 MHz, DMSO-d6) δ 12.06 (br. s., 296[(1S)-1-phenylethyl]- 1H), 8.34 (d, J = 7.89 Hz, 1H), 7.94 (s, 1H),1H-pyrrolo[2,3- 7.37-7.45 (m, 2H), 7.28-7.36 (m, 3H), 7.23 (d, J = 7.48Hz, c]pyridine-4- 1H), 6.67 (s, 1H), 5.06-5.21 (m, 1H), carboxamide 3.57(s, 3H), 1.47 (d, J = 7.06 Hz, 3H).

Example 2656-methyl-7-oxo-N-(6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine

A round bottomed flask was charged with6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1 ml, 6.68 mmol),isopropanol (70 mL), sodium cyanoborohydride (2.94 g, 46.8 mmol), andammonium acetate (15.46 g, 201 mmol). The mixture was stirred at roomtemperature for 4 h and then heated to reflux overnight. After cooling,the reaction was quenched with 1 N sodium hydroxide (100 mL) andextracted with dichloromethane (3×50 mL). The combined organic extractswere washed with water, dried with sodium sulfate, and concentratedunder reduced pressure to give a crude residue that contained6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine. This material was useddirectly in the following amide bond formation.

Step 2:6-methyl-7-oxo-N-(6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

The following example was prepared in a similar fashion to Example 256using 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine (synthesis step 1).¹H NMR (400 MHz, DMSO-d6) δ 12.00-12.13 (m, 1H), 8.37-8.46 (m, 1H), 8.07(s, 1H), 7.29-7.33 (m, 1H), 7.22-7.28 (m, 1H), 7.13 (d, J=4.57 Hz, 3H),6.66-6.72 (m, 1H), 5.17-5.27 (m, 1H), 3.60 (s, 3H), 2.78-2.94 (m, 2H),1.60-2.01 (m, 4H), 1.21-1.36 (m, 2H). LCMS M/Z (M+H) 336.

Example 2666-methyl-7-oxo-N-(6,7,8,9-tetrahydro-5Hbenzo[7]annulen-5-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

The following example was prepared in a similar fashion to Example 159using6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylicacid (Intermediate F). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 7.24(s, 1H), 6.57 (s, 1H), 6.05-5.90 (m, 2H), 5.16 (dq, J=10.3, 1.5 Hz, 1H),5.04 (dq, J=17.1, 1.6 Hz, 1H), 4.61 (dd, J=4.3, 2.7 Hz, 2H), 4.52 (d,J=13.2 Hz, 2H), 2.82-2.74 (m, 5H), 2.37-2.21 (m, 7H), 1.91-1.79 (m, 1H),1.73-1.63 (m, 4H), 0.98-0.80 (m, 4H). LCMS M/Z (M+H) 461.

Example 2676-allyl-N-(1-(2-cyclopropyl-6-methylpyrimidin-4-yl)piperidin-4-yl)-N,2-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

The following example was prepared in a similar fashion to Example 159using6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylicacid (Intermediate F). 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.24(s, 1H), 6.48 (s, 1H), 6.05-5.90 (m, 2H), 5.16 (dq, J=10.3, 1.4 Hz, 1H),5.04 (dq, J=17.0, 1.6 Hz, 1H), 4.61 (dt, J=5.8, 1.5 Hz, 2H), 4.48 (d,J=13.1 Hz, 2H), 4.31 (s, 0H), 2.92-2.71 (m, 5H), 2.32 (s, 3H), 2.18 (s,3H), 1.89 (tt, J=7.9, 4.8 Hz, 1H), 1.73-1.61 (m, 4H), 0.93-0.77 (m, 4H).LCMS M/Z (M+H) 461.

Example 2686-allyl-N,2-dimethyl-N-[1-[6-(2-methyl-3-pyridyl)pyrimidin-4-yl]-4-piperidyl]-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1 tert-butyl(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl)carbamate

To a solution of 4,6-dichloropyrimidine (5.2 g, 35.0 mmol) in DMF (100mL) were added tert-butyl methyl(piperidin-4-yl)carbamate (5.0 g, 23.3mmol) and cesium carbonate (15.2 g, 46.7 mmol). After addition, thereaction mixture was heated at 80° C. for 16 h, at which time LCMSindicated the reaction had gone to completion. The solution was pouredinto ice water, and extracted with ethyl acetate (3×20 mL). The combinedorganic layers were concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography column (Hexanes/ethylacetate=5:1) to give the title compound (7.0 g, 92% yield) as acolorless oil.

Step 2 1-(6-chloropyrimidin-4-yl)-N-methylpiperidin-4-aminehydrochloride

To a solution of tert-butyl(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl) carbamate (7.0 g,21.4 mmol) in ethyl acetate (25 mL) was added a solution of hydrogenchloride (2 N in ethyl acetate, 10 mL). After addition, the mixture wasstirred at room temperature for 3 h, at which time LCMS indicated thereaction had gone to completion. The solution was concentrated underreduced pressure to give the crude title compound (4.5 g, 80% yield) asa yellow oil.

Step 36-allyl-N-(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)-N,2-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a solution of6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylicacid (3.0 g, 12.92 mmol) (Intermediate F) in DMF (100 mL) was added1-(6-chloropyrimidin-4-yl)-N-methylpiperidin-4-amine hydrochloride (4.4g, 16.7 mmol), HATU (5.9 g, 15.5 mmol) and triethylamine (2.6 g, 25.8mmol). The resulting mixture was stirred at ambient temperature for 16h, at which time LCMS indicated the reaction had gone to completion. Thesolution was poured into water (20 mL) and then extracted with ethylacetate (3×100 mL). The combined organic layers were concentrated underreduced pressure. The crude product was purified by silica gelchromatography column (Hexanes/ethyl acetate=1:2) to give the titlecompound (2.8 g, 49% yield) as a yellow oil.

Step 46-allyl-N,2-dimethyl-N-[1-[6-(2-methyl-3-pyridyl)pyrimidin-4-yl]-4-piperidyl]-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

A mixture of6-allyl-N-(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)-N,2-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(100 mg, 0.23 mmol), (2-methylpyridin-3-yl)boronic acid (47 mg, 0.34mmol), cesium carbonate (148 mg, 0.45 mmol) and Pd(dppf)Cl₂ (20 mg, 0.03mmol) in dioxane/H₂O (5:1, 3 mL) was heated at 85° C. under microwaveconditions for 0.5 h, at which time LCMS indicated the reaction had goneto completion. The solvent was evaporated under reduced pressure and thecrude product was purified by reverse phase chromatography (acetonitrile30-50%/0.1% NH₄OH in water) to give the title compound (24 mg, 21%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.95 (s, 1H),8.58 (s, 1H), 8.51-8.50 (m, 1H), 7.81-7.78 (m, 1H), 7.34-7.31 (m, 1H),7.26 (s, 1H), 7.03 (s, 1H), 6.02-5.93 (m, 2H), 5.17-5.14 (m, 1H),5.06-5.02 (m, 1H), 4.62-4.61 (m, 4H), 4.35-4.32 (s, 1H), 3.93-3.89 (m,2H), 2.90 (s, 3H), 2.79 (s, 3H), 2.32 (s, 3H), 1.76-1.72 (m, 4H). LCMSM/Z (M+H) 498.

The following compounds were prepared in a similar fashion to Example268: Examples 269-270

Example Compound Name NMR m/z 269 6-allyl-N-[1-[6-(2- ¹H NMR (400 MHz,DMSO-d₆): δ 8.47 (s, 1 473 furyl)pyrimidin-4-yl]-4- H), 7.88-7.87 (m, 1H), 7.26 (s, 1 H), piperidyl]-N,2-dimethyl-7- 7.20-7.19 (m, 1 H), 7.06(s, 1 H), 6.68-6.66 (m, 1 oxo-1H-pyrrolo[2,3- H), 6.03-5.93 (m, 1 H),5.18-5.15 (m, 1 H), c]pyridine-4-carboxamide 5.07-5.02 (m, 1 H),4.63-4.61 (m, 4 H), 4.37-4.35 (s, 1 H), 2.94-2.90 (m, 2 H), 2.78 (s, 3H), 2.32 (s, 3 H), 1.76-1.72 (m, 4 H). 270 6-allyl-N-[1-[6-(2- ¹H NMR(400 MHz, DMSO-d₆): δ 11.94 (s, 1 517 chlorophenyl)pyrimidin-4- H), 8.58(s, 1 H), 7.56-7.54 (m, 2 H), yl]-4-piperidyl]-N,2- 7.47-7.45 (m, 2 H),7.26 (s, 1 H), 7.04 (s, 1 H), dimethyl-7-oxo-1H- 6.01-5.94 (m, 2 H),5.17-5.14 (m, 1 H), pyrrolo[2,3-c]pyridine-4- 5.06-5.01 (m, 1 H),4.62-4.61 (m, 4 H), carboxamide 4.36-4.33 (s, 1 H), 3.93-3.89 (m, 2 H),2.78 (s, 3 H), 2.32 (s, 3 H), 1.76-1.72 (m, 4 H).

Example 2716-allyl-N,2-dimethyl-7-oxo-N-[1-[6-(2-pyridyl)pyrimidin-4-yl]-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1 tert-butylmethyl(1-(6-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-yl)carbamate

A mixture of tert-butyl(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)(methyl)carbamate (500 mg,1.53 mmol), 2-(tributylstannyl)pyridine (845 mg, 2.30 mmol), Pd(OAc)₂(200 mg, 0.89 mmol) and X-Phos (100 mg, 0.21 mmol) in dioxane (10 mL)was heated at 120° C. under microwave conditions for 30 min, at whichtime LCMS indicated the reaction had gone to completion. After cooled,the reaction mixture was quenched by addition of water (30 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers wereconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography (Hexanes/ethyl acetate=3:1) to give the titlecompound (300 mg, 53% yield) as a colorless oil.

Step 2 N-methyl-1-(6-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-aminehydrochloride

To a solution of tert-butylmethyl(1-(6-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-yl) carbamate (300mg, 0.81 mmol) in ethyl acetate (10 mL) was added hydrogen chloride (2 Nin Ethyl acetate, 10 mL). After addition, the reaction mixture wasstirred at ambient temperature for 2 h, at which time LCMS indicated thereaction had gone to completion. The solvent was evaporated underreduced pressure to give the title compound (200 mg, 81% yield) as ayellow solid.

Step 3:6-allyl-N,2-dimethyl-7-oxo-N-[1-[6-(2-pyridyl)pyrimidin-4-yl]-4-piperidyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

To a solution of6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylicacid (100 mg, 0.43 mmol) in DMF (5 mL) was addedN-methyl-1-(6-(pyridin-2-yl)pyrimidin-4-yl)piperidin-4-aminehydrochloride (158 mg, 0.52 mmol), HATU (213 mg, 0.56 mmol) andN-ethyl-N-isopropylpropan-2-amine (178 mg, 1.38 mmol). After addition,the reaction mixture was stirred at ambient temperature for 8 h, atwhich time LCMS indicated the reaction had gone to completion. Thereaction mixture was diluted with H₂O (10 mL) and extracted with ethylacetate (3×10 mL). The combined organic layers were concentrated underreduced pressure. The crude product was purified by reverse phasechromatography (acetonitrile 45-75%/0.1% NH₄OH in water) to give titlecompound (26 mg, 12%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ 8.67(d, J=4.4 Hz, 1H), 8.57 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.01-7.90 (m,1H), 7.67 (s, 1H), 7.51-7.43 (m, 1H), 7.31 (s, 1H), 6.10-5.97 (m, 2H),5.22 (d, J=10.4 Hz, 1H), 5.14 (d, J=17.2 Hz, 1H), 4.85-4.62 (m, 5H),3.25-3.01 (m, 2H), 2.91 (s, 3H), 2.43 (s, 3H), 1.95-1.82 (m, 4H). LCMSM/Z (M+H) 484.

The following compound was prepared in a similar fashion to Example 271:

Example Compound Name NMR m/z 272 6-allyl-N,2-dimethyl- ¹H NMR (400 MHz,DMSO-d₆): δ 11.94 (s, 1 H), 498 N-[1-[6-(3-methyl-2- 8.58 (s, 1 H),8.50-8.49 (m, 1 H), 7.74-7.72 (m, 1 pyridyl)pyrimidin-4- H), 7.40-7.37(m, 1 H), 7.27 (s, 1 H), 7.17 (s, 1 yl]-4-piperidyl]-7- H), 6.01-5.94(m, 2 H), 5.18-5.15 (m, 1 H), oxo-1H-pyrrolo[2,3- 5.07-5.02 (m, 1H),4.63-4.61 (m, 4 H), 4.38-4.34 (s, 1 c]pyridine-4- H), 3.93-3.89 (m, 2H), 2.79 (s, 3 H), 2.45 (s, 3 carboxamide H), 2.32 (s, 3 H), 2.32 (s, 3H), 1.76-1.72 (m, 4 H).

Example 273 and Example 2741-(6-allyl-2-methyl-7-oxo-,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-4-(4-fluorophenyl)piperazine-2-carboxamide

Step 1 1-tert-butyl 2-methyl4-(4-fluorophenyl)piperazine-1,2-dicarboxylate

In 9 parallel batches, A mixture of tert-butyl 2-methylpiperazine-1,2-dicarboxylate (1.0 g, 4.09 mmol), (4-fluorophenyl)boronicacid (1.72 g, 12.28 mmol), Copper(II) acetate (1.5 g, 8.19 mmol),pyridine (647 mg, 8.19 mmol) and sodium bicarbonate (688 mg, 8.19 mmol)in dichloromethane (50 ml) was stirred at ambient temperature under 02(balloon) for 60 h, at which time LCMS indicated the reaction had goneto completion. The combined solutions were concentrated under reducedpressure. The residue was dissolved in ethyl acetate (50 mL), washedwith water (2×40 mL) and concentrated. The crude product was purified bysilica gel chromatography column (Hexanes/ethyl acetate=5:1) to give thetitle compound (9.8 g, yield 79%) as a brown oil. ¹H NMR (400 MHz,CDCl₃): δ 6.91-6.80 (m, 2H), 6.80-6.62 (m, 2H), 4.86-4.68 (m, 1H),4.05-3.88 (m, 2H), 3.77 (s, 3H), 3.37-3.15 (m, 2H), 2.90-2.86 (m, 1H),2.77-2.68 (m, 1H), 1.49-1.40 (m, 9H). LCMS M/Z (M+H) 338.

Step 2 1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperazine-2-carboxylicacid

To a solution of 1-tert-butyl 2-methyl 4-(4-fluorophenyl)piperazine-1,2-dicarboxylate (5.8 g, 17.14 mmol) in MeOH (80 mL) wasadded a solution of lithium hydroxide (1.64 g, 68.56 mmol) in water (10mL). After addition, the reaction mixture was stirred at 30° C. for 2 h,at which time LCMS indicated the reaction had gone to completion. Thesolvent was evaporated under reduced pressure. The residue was dilutedwith water (20 mL), adjusted to pH=4-5 with 1 N aqueous hydrochloricacid and then extracted with ethyl acetate (2×30 mL). The combinedorganic layers were concentrated to give the crude title compound (5.6g, 99% yield) as a brown oil.

Step 3 tert-butyl 2-carbamoyl-4-(4-fluorophenyl)piperazine-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperazine-2-carboxylic acid (5.6 g, 17.3 mmol) in DMF (100 mL) wasadded N-ethyl-N-isopropylpropan-2-amine (12.3 mL, 69.1 mmol), HATU (9.8g, 25.9 mmol) and NH₄Cl (2.77 g, 51.8 mmol). The reaction mixture wasstirred at ambient temperature for 18 h, at which time LCMS indicatedthe reaction had gone to completion. The solvent was evaporated underreduced pressure. The residue was dissolved in ethyl acetate (200 mL),washed with water (2×70 mL) and concentrated. The crude product waspurified by silica gel chromatography (Hexanes/ethyl acetate=1:1) togive the title compound (4.8 g, 86% yield) as a white solid. ¹H NMR (400MHz, CDCl₃): δ 6.96-6.86 (m, 4H), 6.04 (br., s, 2H), 4.85-4.65 (m, 1H),4.20-4.08 (m, 2H), 3.37-3.14 (m, 2H), 2.83-2.65 (m, 2H), 1.49 (s, 9H).

Step 4 4-(4-fluorophenyl)piperazine-2-carboxamide hydrochloride

To a solution of tert-butyl2-carbamoyl-4-(4-fluorophenyl)piperazine-1-carboxylate (980 mg, 3.03mmol) in methanol (10 mL) was added hydrogen chloride (2 N in ethylacetate, 10 mL). The resulting mixture was stirred at ambienttemperature for 2 h, at which time LCMS indicated the reaction had goneto completion. The solvent was evaporated under reduced pressure to givethe crude title compound (700 mg, 89% yield) as a white solid.

Step 51-(6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-4-(4-fluorophenyl)piperazine-2-carboxamide(fraction 1) and1-(6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-4-(4-fluorophenyl)piperazine-2-carboxamide(fraction 2)

To a solution of6-allyl-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-4-carboxylicacid (Intermediate F) (2.5 g, 12.14 mmol) in DMF (50 mL) was added4-(4-fluorophenyl)piperazine-2-carboxamide (4.0 g, 15.78 mmol), HATU(4.8 g, 12.75 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.3 g, 48.56mmol). The resulting mixture was heated at 60° C. for 18 h, at whichtime LCMS indicated the reaction had gone to completion. The mixture wasquenched by addition of water (80 mL) and the precipitate was collectedby filtration. The solid was washed with water and dried in vacuum togive the mixture of enantiomers (3.1 g, 59% yield) as a brown solid. Theenantiomers were separated by using chiral SFC (SFC80; Chiralpak AD300×50 mm I.D., 5 um; Supercritical CO₂/EtOH+NH₃:H₂O=55/45; 200 ml/min)to give the title compounds as white solids.

Fraction 1 (976 mg, 18% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (s,1H), 7.54 (s, 1H), 7.41-7.16 (m, 2H), 7.14-7.00 (m, 2H), 6.97-6.85 (m,2H), 6.18 (br. s, 1H), 6.00-5.92 (m, 1H), 5.16 (d, J=10.4, 1H), 5.05 (d,J=17.2, 1H), 4.61 (s, 2H), 4.12-4.03 (m, 1H), 3.75-3.37 (m, 4H), 2.89(d, J=9.6, 1H), 2.70-2.58 (m, 1H), 2.32 (s, 3H). LCMS M/Z (M+H) 438. SFCretention time: 0.63 min.

Fraction 2 (833 mg, 16% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.97 (s,1H), 7.53 (s, 1H), 7.40-7.15 (m, 2H), 7.13-7.01 (m, 2H), 6.95-6.86 (m,2H), 6.17 (br. s, 1H), 5.99-5.92 (m, 1H), 5.15 (d, J=10.0, 1H), 5.05 (d,J=16.8, 1H), 4.61 (s, 2H), 4.10-4.01 (m, 1H), 3.70-3.37 (m, 4H), 2.89(d, J=9.6, 1H), 2.69-2.58 (m, 1H), 2.31 (s, 3H). LCMS M/Z (M+H) 438. SFCretention time: 2.15 min.

Example 2756-allyl-N,2-dimethyl-7-oxo-N-tetralin-1-yl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Title compound was prepared in a similar fashion as Example 244 usingIntermediate F. ¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H), 7.36 (s, 1H),7.24-7.08 (m, 4H), 6.06 (s, 1H), 6.03-5.93 (m, 1H), 5.22-4.94 (m, 3H),4.77-4.48 (m, 2H), 2.62 (s, 5H), 2.33 (s, 3H), 2.14-1.80 (m, 4H). LCMSM/Z (M+H) 376.

Example 2766-allyl-N,2-dimethyl-7-oxo-N-tetralin-1-yl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: tert-butyl N-(5,6,7,8-tetrahydroquinolin-5-yl)carbamate

To a 20 mL vial was added 5,6,7,8-tetrahydroquinolin-5-amine (500 mg,3.4 mmol) followed by tert-butoxycarbonyl tert-butyl carbonate (773 mg,3.5 mmol), 6 mL of tetrahydrofuran, and 6 mL of saturated sodiumbicarbonate. The reaction was shaken at room temperature for 1 h. LCMSshowed product formation. The reaction was diluted with ethyl acetate,and washed with water. Organic phase was then concentrated under reducedpressure. The crude product was carried on directly withoutpurification. LCMS M/Z (M+H) 249.

Step 2: N-methyl-5,6,7,8-tetrahydroquinolin-5-amine dihydrochloride

Tert-butyl N-(5,6,7,8-tetrahydroquinolin-5-yl)carbamate (110 mg, 0.44mmol) was taken up with 3 mL of N,N-dimethylformamide, and sodiumhydride 60% in mineral oil (53 mg, 1.33 mmol) was then added. Thereaction was stirred for 15 minutes, then iodomethane (0.028 mL, 0.44mmol) was added. The reaction was capped and shaken at room temperaturefor 30 min. LCMS showed single addition.

The reaction was diluted with ethyl acetate, and quenched with water.The phases were separated, and the aqueous further extracted with ethylacetate. The combined organics were concentrated under reduced pressure.LCMS M/Z (M+H) 263.

The crude product was then taken up with 5 mL of methanol followed by 5mL of 4N HCl/dioxane. The reaction was stirred at room temperature for 1h then concentrated under reduced pressure. The crude was carried on tothe next reaction without purification.

Step 3:6-allyl-N,2-dimethyl-7-oxo-N-tetralin-1-yl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Title compound was prepared in a similar fashion to Example 244, usingIntermediate F. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.37 (d,J=4.9 Hz, 1H), 7.52-7.46 (m, 1H), 7.39 (s, 1H), 7.24 (dd, J=7.8, 4.7 Hz,1H), 6.07 (s, 1H), 5.97 (ddd, J=15.8, 10.5, 5.2 Hz, 1H), 5.14 (d, J=10.3Hz, 1H), 5.03 (d, J=17.3 Hz, 1H), 4.63 (s, 2H), 2.89 (d, J=0.5 Hz, 2H),2.64 (s, 3H), 2.33 (s, 3H), 2.16-1.88 (m, 314). LCMS M/Z (M+H) 377.

The following compounds were prepared in a similar fashion to Example276: Examples 277-282

Example Compound Name NMR m/z 277 6-allyl-N-chroman-4- 1H NMR (400 MHz,DMSO-d6) δ 11.94 (s, 1H), 378 yl-N,2-dimethyl-7- 7.39 (s, 1H), 7.20-7.10(m, 1H), 7.09-7.02 (m, oxo-1H-pyrrolo[2,3- 1H), 6.93 (td, J = 7.5, 1.2Hz, 1H), 6.79 (d, J = 8.0 Hz, c]pyridine-4- 1H), 6.07 (s, 1H), 5.98(ddt, J = 16.1, 10.5, 5.4 Hz, carboxamide 1H), 5.14 (d, J = 10.1 Hz,1H), 5.10-5.00 (m, 1H), 4.63 (s, 2H), 4.31 (s, 1H), 4.15 (s, 1H), 2.64(s, 3H), 2.33 (d, J = 0.8 Hz, 3H), 2.31-2.18 (m, 1H), 2.17-2.03 (m, 1H).278 6-allyl-N-(7- 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 396fluorochroman-4-yl)- 7.44 (s, 1H), 7.06-6.96 (m, 1H), 6.87-6.78 (m,N,2-dimethyl-7-oxo- 2H), 6.12-6.02 (m, 1H), 5.97 (ddd, J = 17.2, 10.4,1H-pyrrolo[2,3- 5.3 Hz, 1H), 5.14 (dd, J = 10.0, 1.7 Hz, 1H),c]pyridine-4- 5.05 (dd, J = 17.1, 1.8 Hz, 1H), 4.63 (d, J = 5.4 Hz, 2H),carboxamide 4.32 (d, J = 11.1 Hz, 1H), 4.14 (s, 1H), 2.67 (s, 3H), 2.34(d, J = 0.9 Hz, 3H), 2.30-2.15 (m, 1H), 2.14-2.05 (m, 1H). 2796-allyl-N-(4,4- 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 404dimethyltetralin-1- 7.39 (s, 2H), 7.19 (q, J = 6.8 Hz, 2H), 7.05 (s,1H), yl)-N,2-dimethyl-7- 6.02 (d, J = 39.7 Hz, 2H), 5.09 (d, J = 40.2Hz, oxo-1H-pyrrolo[2,3- 2H), 4.66 (s, 2H), 2.63 (s, 3H), 2.39-2.28 (m,c]pyridine-4- 3H), 2.06 (d, J = 5.2 Hz, 1H), 1.91 (dp, J = 13.1,carboxamide 5.1, 4.5 Hz, 1H), 1.74 (s, 2H), 1.25 (s, 6H). Enantiomer 1280 6-allyl-N-(4,4- 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 404dimethyltetralin-1- 7.39 (s, 2H), 7.19 (q, J = 6.8 Hz, 2H), 7.05 (s,1H), yl)-N,2-dimethyl-7- 6.02 (d, J = 39.7 Hz, 2H), 5.09 (d, J = 40.2Hz, oxo-1H-pyrrolo[2,3- 2H), 4.66 (s, 2H), 2.63 (s, 3H), 2.39-2.28 (m,c]pyridine-4- 3H), 2.06 (d, J = 5.2 Hz, 1H), 1.91 (dp, J = 13.1,carboxamide 5.1, 4.5 Hz, 1H), 1.74 (s, 2H), 1.25 (s, 6H). Enantiomer 2281 6-allyl-N-(6- ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 406methoxytetralin-1- 7.44-7.20 (m, 1H), 7.12-6.91 (m, 1H),yl)-N,2-dimethyl-7- 6.84-6.72 (m, 1H), 6.72-6.57 (m, 1H), 6.14-5.88 (m,oxo-1H-pyrrolo[2,3- 2H), 5.86-5.60 (m, 1H), 5.24-4.83 (m, 3H),c]pyridine-4- 4.80-4.47 (m, 2H), 3.72 (s, 3H), 2.87-2.57 (m,carboxamide, 5H), 2.33 (s, 3H), 2.19-1.75 (m, 4H). Enantiomer 1 2826-allyl-N-(6- ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 406methoxytetralin-1- 7.44-7.20 (m, 1H), 7.12-6.91 (m, 1H),yl)-N,2-dimethyl-7- 6.84-6.72 (m, 1H), 6.72-6.57 (m, 1H), 6.14-5.88 (m,oxo-1H-pyrrolo[2,3- 2H), 5.86-5.60 (m, 1H), 5.24-4.83 (m, 3H),c]pyridine-4- 4.80-4.47 (m, 2H), 3.72 (s, 3H), 2.87-2.57 (m,carboxamide, 5H), 2.33 (s, 3H), 2.19-1.75 (m, 4H). Enantiomer 2

Example 2836-allyl-N,2-dimethyl-7-oxo-N-(5,6,7,8-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Step 1: N-methyl-5,6,7,8-tetrahydroisoquinolin-5-amine

To a 20 mL vial was added 7,8-dihydro-6H-isoquinolin-5-one (200 mg, 1.36mmol) followed by methanamine hydrochloride (275 mg, 4.08 mmol,),diisopropylethylamine (527 mg, 4.08 mmol), and 4 mL of1,2-dichloroethane. The reaction was capped and shaken at 50° C. for 1h. Sodium cyanoborohydride (261 mg, 4.08 mmol) was then added, and thereaction was capped and shaken at 50° C. for 72 h. LCMS shows desiredproduct. The reaction was then diluted with DCM, and washed with 1NNaOH. The organic phase was concentrated under reduced pressure yieldingcrude product, which was carried on without purification. LCMS M/Z (M+H)162.

Step 2:6-allyl-N,2-dimethyl-7-oxo-N-(5,6,7,8-tetrahydroisoquinolin-5-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide

Title compound was prepared in a similar fashion to Example 244, usingIntermediate F. ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.36 (d,J=5.2 Hz, 2H), 7.40 (s, 1H), 7.08 (d, J=4.9 Hz, 1H), 6.08 (s, 1H), 5.97(s, 1H), 5.21-4.98 (m, 2H), 4.63 (s, 2H), 2.74 (s, 2H), 2.66 (s, 3H),2.34 (s, 3H), 2.16-1.75 (m, 4H). LCMS M/Z (M+H) 377.

The following compounds were prepared in a similar fashion to Example283: Examples 284-291

Example Compound Name NMR m/z 284 6-allyl-N-(7- ¹H NMR (400 MHz,DMSO-d₆) δ 11.96 (s, 394 fluorotetralin-1-yl)-N,2- 1H), 7.42 (s, 1H),7.27-7.12 (m, 1H), dimethyl-7-oxo-1H- 7.08-6.96 (m, 1H), 6.90-6.72 (m,1H), pyrrolo[2,3-c]pyridine-4- 6.12-5.90 (m, 2H), 5.83-5.55 (m, 1H),5.22-4.97 (m, carboxamide 2H), 4.64 (s, 2H), 2.81-2.59 (m, 5H), 2.33 (s,3H), 2.23-1.81 (m, 4H). 285 6-allyl-N,2-dimethyl-N- ¹H NMR (400 MHz,DMSO-d₆) δ 11.96 (s, 390 (5-methyltetralin-1-yl)-7- 1H), 7.32 (d, J =32.2 Hz, 1H), 7.13-6.81 (m, oxo-1H-pyrrolo[2,3- 3H), 6.01 (d, J = 38.2Hz, 2H), 5.77 (s, 1H), c]pyridine-4- 5.07 (d, J = 43.4 Hz, 3H), 4.65 (s,2H), 2.65 (d, carboxamide J = 19.5 Hz, 5H), 2.33 (s, 3H), 2.26 (s, 4H),2.10-1.81 (m, 4H). 286 6-allyl-N-(5- ¹H NMR (400 MHz, DMSO-d₆) δ 11.95(s, 394 fluorotetralin-1-yl)-N,2- 1H), 7.38 (s, 1H), 7.32-7.17 (m, 1H),dimethyl-7-oxo-1H- 7.12-6.86 (m, 2H), 6.15-5.86 (m, 2H), 5.77 (s,pyrrolo[2,3-c]pyridine-4- 1H), 5.24-4.92 (m, 2H), 4.65 (s, 2H),carboxamide Enantiomer 1 2.86-2.56 (m, 5H), 2.33 (s, 3H), 2.16-1.73 (m,4H). 287 6-allyl-N,2-dimethyl-N- 1H NMR (400 MHz, DMSO-d6) δ 390(7-methyltetralin-1-yl)-7- 12.00-11.86 (m, 1H), 7.35 (s, 1H), 7.07 (dd,J = 22.6, oxo-1H-pyrrolo[2,3- 7.4 Hz, 2H), 6.94 (s, 1H), 6.01 (d, J =35.4 Hz, c]pyridine-4- 2H), 5.79 (s, 1H), 5.23-4.88 (m, 2H), 4.65 (s,carboxamide Enantiomer 2 2H), 2.60 (s, 4H), 2.33 (s, 3H), 2.18 (s, 3H),2.10-1.78 (m, 4H). 288 6-allyl-N-(5- ¹H NMR (400 MHz, DMSO-d₆) δ 11.94(s, 406 methoxytetralin-1-yl)- 1H), 7.36 (s, 1H), 7.25-7.12 (m, 1H),N,2-dimethyl-7-oxo-1H- 6.89-6.76 (m, 1H), 6.76-6.64 (m, 1H),pyrrolo[2,3-c]pyridine-4- 6.13-5.88 (m, 2H), 5.88-5.69 (m, 1H),5.25-4.87 (m, carboxamide Enantiomer 1 3H), 4.78-4.48 (m, 2H), 3.85-3.63(m, 3H), 2.83-2.56 (m, 5H), 2.33 (s, 3H), 2.06-1.73 (m, 4H). 2896-allyl-N-(5- ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 406methoxytetralin-1-yl)- 1H), 7.36 (s, 1H), 7.25-7.12 (m, 1H),N,2-dimethyl-7-oxo-1H- 6.89-6.76 (m, 1H), 6.76-6.64 (m, 1H),pyrrolo[2,3-c]pyridine-4- 6.13-5.88 (m, 2H), 5.88-5.69 (m, 1H),5.25-4.87 (m, carboxamide Enantiomer 2 3H), 4.78-4.48 (m, 2H), 3.85-3.63(m, 3H), 2.83-2.56 (m, 5H), 2.33 (s, 3H), 2.06-1.73 (m, 4H). 2906-allyl-N,2-dimethyl-7- 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 377oxo-N-(5,6,7,8- 1H), 8.48-8.20 (m, 2H), 7.43 (s, 1H), 7.14 (d,tetrahydroisoquinolin-8- J = 4.8 Hz, 1H), 6.20-5.86 (m, 2H), 5.76 (s,yl)-1H-pyrrolo[2,3- 1H), 5.09 (dd, J = 39.2, 13.5 Hz, 2H), 4.65 (s,c]pyridine-4- 2H), 2.67 (s, 5H), 2.34 (s, 3H), 2.24-1.78 (m, carboxamideEnantiomer 1 4H). 291 6-allyl-N,2-dimethyl-7- 1H NMR (400 MHz, DMSO-d6)δ 11.96 (s, 377 oxo-N-(5,6,7,8- 1H), 8.48-8.20 (m, 2H), 7.43 (s, 1H),7.14 (d, tetrahydroisoquinolin-8- J = 4.8 Hz, 1H), 6.20-5.86 (m, 2H),5.76 (s, yl)-1H-pyrrolo[2,3- 1H), 5.09 (dd, J = 39.2, 13.5 Hz, 2H), 4.65(s, c]pyridine-4- 2H), 2.67 (s, 5H), 2.34 (s, 3H), 2.24-1.78 (m,carboxamide Enantiomer 2 4H).

Example 292

Synthesis of biotinylated probe compound (1000) for TAF assay describedbelow.

Step 1: 2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol) inmethanol (1.0 L) was added dropwise (2 h) to a stirred and cooled (0°C.) solution of sodium methoxide (250 g, 4.63 mol) in methanol (850 mL).After addition, the mixture was heated to reflux for 23 h, at which timeTLC indicated the reaction had gone to completion. The mixture wasconcentrated under reduced pressure to a volume of approximately 900 mL,and quenched by addition of water (1.5 L). The resulting solid wascollected by filtration, washed with water and dried under reducedpressure to give the title compound (250 g, 100% yield) as a brownsolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J=5.2 Hz, 1H), 7.10 (d,J=5.6 Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H).

Step 2: 5-bromo-2-methoxy-4-methyl-3-nitropyridine

Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid (1.5L) at ambient temperature and then Br₂ (639 g, 4.00 mol) was addeddropwise (30 min). After addition, the mixture was heated at 80° C. for12 h, at which time TLC indicated the reaction had gone to completion.The mixture was cooled (0° C.) and quenched by sequential addition of10% aqueous (1.5 L) and saturated aqueous Na₂SO₃ (1.5 L). The resultingsolid was collected by filtration washed with water, and dried underreduced pressure to give the title compound (302 g, 82.2% yield) as alight yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 3.94 (s,3H), 2.29 (s, 3H).

Step 3:(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine

DMF-DMA (600 mL) was slowly added to a stirred and heated (80° C.)solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol)in DMF (1.1 L). After addition, the mixture was heated at 95° C. for 5h, at which time TLC indicated the reaction had gone to completion. Themixture was cooled to room temperature and poured into ice-cold water (3L). The resulting red solid was collected by filtration, washed withwater, and dried under reduced pressure to give the title compound (167g, 100% yield) as red solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H),7.05 (d, J=13.6 Hz, 1H), 7.05 (d, J=13.6 Hz, 1H), 4.80 (d, J=13.2 Hz,1H), 3.88 (s, 3H), 2.90 (s, 6H).

Step 4: 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

A mixture of2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (50.0g, 165 mmol), Fe (50.0 g, 893 mmol) and NH₄Cl (50.0 g, 943 mmol) inmethanol/H₂O (1900/250 mL) was heated at reflux for 7 h, at which timeLCMS indicated that the reaction had gone to completion. The mixture wasfiltered while hot and the cake was washed with methanol (3×200 mL). Thecombined filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel chromatography (petroleumether: Ethyl acetate=5:1) to give the crude product. This crude materialwas triturated with acetonitrile to give the title compound (37.4 g,99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7, 228.7.

Step 5: 4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine

A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g, 0.15mol) in THF (700 mL) was added dropwise to a stirred and cooled (0° C.)solution of sodium hydride (60%, 19.2 g, 0.48 mol) in THF (700 mL).After addition, the mixture was stirred at room temperature for 1 h, andthen cooled again to 0° C. Tosyl chloride (38.0 g, 0.20 mol) in THF (700mL) was added dropwise and the resulting mixture was stirred at ambienttemperature for 2 h. The reaction was quenched by addition of saturatedaqueous ammonium chloride (1.0 L), and then extracted with ethyl acetate(3×600 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was triturated withacetonitrile to give the title compound (51.2 g, 88.9% yield) as a brownsolid. This crude material was used in the next step without furtherpurification.

Step 6: 4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one

HBr (40% aqueous, 1.1 L) was added to a solution of4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (102.5 g,0.27 mol) in ethanol (200 mL). After addition, the mixture was heated at90° C. for 2 h, at which time TLC indicated that the reaction had goneto completion. The mixture was cooled to 0° C. and the resulting whitesolid was collected by filtration. This solid was washed with water anddried under vacuum to give the title compound (87.5 g, 88.6% yield) as alight brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.48 (s, 1H), 8.01 (d,J=3.6 Hz, 1H), 8.90 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.32 (s,1H), 6.57 (d, J=3.2 Hz, 1H), 2.34 (s, 3H).

Step 7: 4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one

Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirredsuspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(Intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g, 54.6mmol) in dioxane (250 mL). After addition, the reaction mixture wasstirred at room temperature for 18 h, at which time LCMS indicated thereaction had gone to completion. The solvent was evaporated underreduced pressure, and the residue was diluted with water (200 mL). Themixture was extracted with EtOAc (3×200 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=3:1) to give the title compound (14.0 g,81.4% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.03 (d,J=3.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.78 (s, 1H), 7.39 (d, J=8.4 Hz,2H), 6.57 (d, J=3.6 Hz, 1H), 3.35 (s, 3H), 2.35 (s, 3H).

Step 8:

A 50 mL vial was charged with a magnetic stir bar,4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (0.281 g,0.737 mmol), 1,4-dioxane (3.69 ml, 0.737 mmol), water (0.5 ml, 27.8mmol), K₂CO₃ (0.306 g, 2.211 mmol),4-(tertbutoxycarbonylamino)phenylboronic acid (0.227 g, 0.958 mmol), andPd(PPh₃)₄ (0.085 g, 0.074 mmol). The vial was purged, placed under anatmosphere of nitrogen and heated to 95° C. with stirring for 12 hbefore being allowed to cool to room temperature. The reaction was thendiluted with water (20 ml). A precipitate formed which was collected viavacuum filtration using a Buchner funnel. The solids were washed withadditional water (2×25 mL), dried, and collected. This material wassuspended in methanol (˜5 mL) and treated with KOH (200 mg). After 2 hthe MeOH was removed in vacuo and the crude material was suspended inwater (˜20 mL) and the resulting solids were collected via vacuumfiltration using a Buchner funnel. The solids were washed withadditional water, were collected, and dried in vacuo to affordtert-butyl4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate(362 mg, 0.907 mmol) as a light yellow solid. LCMS M/Z (M+H) 494.

Step 9:

A 50 mL round bottom flask was charged with a magnetic stir bar,tert-butyl4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate(350 mg, 1.031 mmol), MeOH (2.062 mL, 1.031 mmol), and HCl (1.031 mL,4.12 mmol) (4N in dioxane). The reaction was then allowed to stir at rtfor 4 h before being diluted with dioxane (25 mL). A precipitate formedwhich was collected via vacuum filtration using a Buchner funnel, washedwith additional dioxane, and dried in vacuo to afford4-(4-aminophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (188 mg,0.786 mmol, 76% yield) as a white solid. LCMS M/Z (M+H) 240.

Step 10:

A 25 mL vial was charged with a magnetic stir bar,4-(4-aminophenyl)-6-methyl-1Hpyrrolo[2,3-c]pyridin-7(6H)-one (0.038 g,0.159 mmol), anhydrous DMF (0.794 ml, 0.159 mmol), DIPEA (0.139 ml,0.794 mmol),17-oxo-21-((3aS,4S,6aR)-2-oxohexahydro-1Hthieno[3,4-d]imidazol-4-yl)-4,7,10,13-tetraoxa-16-azahenicosan-1-oicacid (0.078 g, 0.159 mmol), and HATU (0.075 g, 0.199 mmol). The crudereaction mixture was directly purified via reverse phase HPLC to affordN-(4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide(31 mg, 0.041 mmol, 26.0% yield). LCMS M/Z (M+2H)/2 357.

Example 293

Synthesis of biotinylated probe compound (1001) for CECR2 assaydescribed below.

Step 1: 2-methoxy-4-methyl-3-nitropyridine

A solution of 2-chloro-4-methyl-3-nitropyridine (250 g, 1.45 mol) inmethanol (1.0 L) was added dropwise (2 h) to a stirred and cooled (0°C.) solution of sodium methoxide (250 g, 4.63 mol) in methanol (850 mL).After addition, the mixture was heated to reflux for 23 h, at which timeTLC indicated the reaction had gone to completion. The mixture wasconcentrated under reduced pressure to a volume of approximately 900 mL,and quenched by addition of water (1.5 L). The resulting solid wascollected by filtration, washed with water and dried under reducedpressure to give the title compound (250 g, 100% yield) as a brownsolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J=5.2 Hz, 1H), 7.10 (d,J=5.6 Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H).

Step 2: 5-bromo-2-methoxy-4-methyl-3-nitropyridine

Sodium acetate (365 g, 5.37 mol) was added to a stirred solution of2-methoxy-4-methyl-3-nitropyridine (250 g, 1.49 mol) in acetic acid (1.5L) at ambient temperature and then Br₂ (639 g, 4.00 mol) was addeddropwise (30 min). After addition, the mixture was heated at 80° C. for12 h, at which time TLC indicated the reaction had gone to completion.The mixture was cooled (0° C.) and quenched by sequential addition of10% aqueous (1.5 L) and saturated aqueous Na₂SO₃ (1.5 L). The resultingsolid was collected by filtration washed with water, and dried underreduced pressure to give the title compound (302 g, 82.2% yield) as alight yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 3.94 (s,3H), 2.29 (s, 3H).

Step 3:(E)-2-(5-bromo-2-methoxy-3-nitro-4-pyridyl)-N,N-dimethyl-ethenamine

DMF-DMA (600 mL) was slowly added to a stirred and heated (80° C.)solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (134 g, 0.54 mol)in DMF (1.1 L). After addition, the mixture was heated at 95° C. for 5h, at which time TLC indicated the reaction had gone to completion. Themixture was cooled to room temperature and poured into ice-cold water (3L). The resulting red solid was collected by filtration, washed withwater, and dried under reduced pressure to give the title compound (167g, 100% yield) as red solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H),7.05 (d, J=13.6 Hz, 1H), 7.05 (d, J=13.6 Hz, 1H), 4.80 (d, J=13.2 Hz,1H), 3.88 (s, 3H), 2.90 (s, 6H).

Step 4: 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

A mixture of2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (50.0g, 165 mmol), Fe (50.0 g, 893 mmol) and NH₄Cl (50.0 g, 943 mmol) inmethanol/H₂O (1900/250 mL) was heated at reflux for 7 h, at which timeLCMS indicated that the reaction had gone to completion. The mixture wasfiltered while hot and the cake was washed with methanol (3×200 mL). Thecombined filtrate was concentrated under reduced pressure, and theresulting residue was purified by silica gel chromatography (petroleumether: Ethyl acetate=5:1) to give the crude product. This crude materialwas triturated with acetonitrile to give the title compound (37.4 g,99.5% yield) as a light brown solid. LCMS M/Z (M+H) 226.7, 228.7.

Step 5: 4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine

A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (34.3 g, 0.15mol) in THF (700 mL) was added dropwise to a stirred and cooled (0° C.)solution of sodium hydride (60%, 19.2 g, 0.48 mol) in THF (700 mL).After addition, the mixture was stirred at room temperature for 1 h, andthen cooled again to 0° C. Tosyl chloride (38.0 g, 0.20 mol) in THF (700mL) was added dropwise and the resulting mixture was stirred at ambienttemperature for 2 h. The reaction was quenched by addition of saturatedaqueous ammonium chloride (1.0 L), and then extracted with ethyl acetate(3×600 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was triturated withacetonitrile to give the title compound (51.2 g, 88.9% yield) as a brownsolid. This crude material was used in the next step without furtherpurification.

Step 6: 4-bromo-1-(p-tolylsulfonyl)-6H-pyrrolo[2,3-c]pyridin-7-one

HBr (40% aqueous, 1.1 L) was added to a solution of4-bromo-7-methoxy-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (102.5 g,0.27 mol) in ethanol (200 mL). After addition, the mixture was heated at90° C. for 2 h, at which time TLC indicated that the reaction had goneto completion. The mixture was cooled to 0° C. and the resulting whitesolid was collected by filtration. This solid was washed with water anddried under vacuum to give the title compound (87.5 g, 88.6% yield) as alight brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 11.48 (s, 1H), 8.01 (d,J=3.6 Hz, 1H), 8.90 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.32 (s,1H), 6.57 (d, J=3.2 Hz, 1H), 2.34 (s, 3H).

Step 7: 4-bromo-6-methyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one

Methyl iodide (24.5 g, 172.8 mmol) was added dropwise to a stirredsuspension of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one(Intermediate A) (16.7 g, 45.5 mmol) and cesium carbonate (17.8 g, 54.6mmol) in dioxane (250 mL). After addition, the reaction mixture wasstirred at room temperature for 18 h, at which time LCMS indicated thereaction had gone to completion. The solvent was evaporated underreduced pressure, and the residue was diluted with water (200 mL). Themixture was extracted with EtOAc (3×200 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=3:1) to give the title compound (14.0 g,81.4% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.03 (d,J=3.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.78 (s, 1H), 7.39 (d, J=8.4 Hz,2H), 6.57 (d, J=3.6 Hz, 1H), 3.35 (s, 3H), 2.35 (s, 3H).

Step 8:

A 50 mL vial was charged with a magnetic stir bar,4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (0.281 g,0.737 mmol), 1,4-dioxane (3.69 ml, 0.737 mmol), water (0.5 ml, 27.8mmol), K₂CO₃ (0.306 g, 2.211 mmol),4-(tertbutoxycarbonylamino)phenylboronic acid (0.227 g, 0.958 mmol), andPd(PPh₃)₄ (0.085 g, 0.074 mmol). The vial was purged, placed under anatmosphere of nitrogen and heated to 95° C. with stirring for 12 hbefore being allowed to cool to room temperature. The reaction was thendiluted with water (20 ml). A precipitate formed which was collected viavacuum filtration using a Buchner funnel. The solids were washed withadditional water (2×25 mL), dried, and collected. This material wassuspended in methanol (˜5 mL) and treated with KOH (200 mg). After 2 hthe MeOH was removed in vacuo and the crude material was suspended inwater (˜20 mL) and the resulting solids were collected via vacuumfiltration using a Buchner funnel. The solids were washed withadditional water, were collected, and dried in vacuo to affordtert-butyl4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate(362 mg, 0.907 mmol) as a light yellow solid. LCMS M/Z (M+H) 494.

Step 9:

A 50 mL round bottom flask was charged with a magnetic stir bar,tert-butyl4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenylcarbamate(350 mg, 1.031 mmol), MeOH (2.062 mL, 1.031 mmol), and HCl (1.031 mL,4.12 mmol) (4N in dioxane). The reaction was then allowed to stir at rtfor 4 h before being diluted with dioxane (25 mL). A precipitate formedwhich was collected via vacuum filtration using a Buchner funnel, washedwith additional dioxane, and dried in vacuo to afford4-(4-aminophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (188 mg,0.786 mmol, 76% yield) as a white solid. LCMS M/Z (M+H) 240.

Step 10:

A 25 mL vial was charged with a magnetic stir bar,4-(4-aminophenyl)-6-methyl-1Hpyrrolo[2,3-c]pyridin-7(6H)-one (0.038 g,0.159 mmol), anhydrous DMF (0.794 ml, 0.159 mmol), DIPEA (0.139 ml,0.794 mmol),17-oxo-21-((3aS,4S,6aR)-2-oxohexahydro-1Hthieno[3,4-d]imidazol-4-yl)-4,7,10,13-tetraoxa-16-azahenicosan-1-oicacid (0.078 g, 0.159 mmol), and HATU (0.075 g, 0.199 mmol). The crudereaction mixture was directly purified via reverse phase HPLC to affordN-(4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-1-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide (31 mg, 0.041 mmol, 26.0% yield). LCMS M/Z (M+2H)/2 357.

Example 294

The inhibitory activity of representative compounds against bromodomainscan be evaluated using known methods or using one of the following assayprotocols.

IC₅₀ Measurements for Inhibitors Using BRD4 AlphaLisa Binding Assay

His/Flag epitope tagged BRD4 BD1₄₂₋₁₆₈ was cloned, expressed, andpurified to. BRD4 binding and inhibition was assessed by monitoring theengagement of biotinylated H4-tetraacetyl peptide (New England Peptide,NEP2069-1/13) with the target using the AlphaLisa technology(Perkin-Elmer). Specifically, in a 384 well ProxiPlate BRD4(BD1) (30 nMfinal) was combined with peptide (200 nM final) in 40 mM HEPES (pH 7.0),40 mM NaCl, 1 mM DTT, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 eitherin the presence of DMSO (final 1.2% DMSO) or compound dilution series inDMSO. After 20 minutes incubation at room temperature Alpha streptavidindonor beads and AlphaLisa anti-Flag acceptor beads were added to a finalconcentration of 10 ug/mL each. After three hours equilibration plateswere read on an Envision instrument and IC₅₀s calculated using a fourparameter non-linear curve fit.

IC₅₀ Measurements for Inhibitors Using BRD9 AlphaLisa Binding Assay

His/Flag epitope tagged BRD9₁₃₄₋₂₃₉ was cloned, expressed, and purifiedto homogeneity. BRD9 binding and inhibition was assessed by monitoringthe engagement of biotinylated H4-tetraacetyl peptide (New EnglandPeptide, NEP2069-11/13) with the target using the AlphaLisa technology(Perkin-Elmer). Specifically, in a 384 well ProxiPlate BRD9 (50 nMfinal) was combined with peptide (3 nM final) in 50 mM HEPES (pH 7.5),150 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 eitherin the presence of DMSO (final 0.8% DMSO) or compound dilution series inDMSO. After 20 minutes incubation at room temperature AlphaLisaStreptavidin Acceptor Beads (Perkin-AL125C) and AlphaLisa Nickel donorbeads (Perkin AS 10 ID) were added to a final concentration of 15 ug/mLeach. After ninety minutes of equilibration in the dark, the plates wereread on an Envision instrument and IC₅₀s calculated using a fourparameter non-linear curve fit.

IC₅₀ Measurements for Inhibitors Using TAF1-BD2 TR-FRET Binding Assay

His/Flag epitope tagged TAF1-BD2₁₅₀₄₋₁₆₃₅ was cloned, expressed, andpurified to homogeneity. TAF1-BD2 binding and inhibition was assessed bymonitoring the engagement of a biotinylated small molecule compound 1000(Example 292) with the target using the TR-FRET assay technology(Perkin-Elmer). Specifically, in a 384 well ProxiPlate TAF1-BD2 (6 nMfinal) was combined with biotin-ligand (50 nM final) in 50 mM HEPES (pH7.5), 50 mM NaCl, 1 mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35either in the presence of DMSO (final 0.2% DMSO) or compound dilutionseries in DMSO. After 10 minutes incubation at room temperature, amixture Eu-W1024 Anti-6×His antibody (Perkin Elmer AD0110) andSureLight™ Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer CR130-100)were added to a final concentrations of 0.2 nMolar antibody and 25nMolar APC-SA, respectively. After twenty minutes of equilibration, theplates were read on an Envision instrument and IC₅₀s calculated using afour parameter non-linear curve fit. Novel compound 1000 and theTAF1-BD2 TR-FRET Binding Assay described above represent additionalembodiments of the invention.

IC50 Measurements for Inhibitors Using CECR2 TR-FRET Binding Assay

His/Flag epitope tagged CECR2₄₂₄₋₅₃₈ was cloned, expressed, and purifiedto homogeneity. CECR2 binding and inhibition was assessed by monitoringthe engagement of a biotinylated small molecule compound 1001 (Example293) with the target using the TR-FRET assay technology (Perkin-Elmer).Specifically, in a 384 well ProxiPlate CECR2 (1.5 nM final) was combinedwith biotin-ligand (25 nM final) in 50 mM HEPES (pH 7.5), 50 mM NaCl, 1mM TCEP, 0.01% (w/v) BSA, and 0.008% (w/v) Brij-35 either in thepresence of DMSO (final 0.2% DMSO) or compound dilution series in DMSO.After 15 minutes incubation at room temperature, a mixture Eu-W1024Anti-6×His antibody (Perkin Elmer AD0110) and SureLight™Allophycocyanin-Streptavidin (APC-SA, Perkin Elmer CR130-100) were addedto a final concentrations of 0.2 nMolar antibody and 12.5 nMolar APC-SA,respectively. After forty minutes of equilibration, the plates were readon an Envision instrument and IC₅₀s calculated using a four parameternon-linear curve fit. Novel compound 1001 and the CECR2 TR-FRET BindingAssay described above represent additional embodiments of the invention.

Data for representative compounds of formula (I) from the four assaysdescribed above is provided in the following table.

Example Assay IC50 (uM) 8 BRD4 4.9 28 BRD4 19 31 BRD4 17 32 BRD4 9.8 46BRD4 6.4 50 BRD4 16 55 BRD4 9.5 57 BRD4 4.1 64 BRD4 8.0 92 BRD4 8.4 93BRD4 2.9 94 BRD4 3.1 95 BRD4 11 96 BRD4 5.0 101 BRD4 17 105 BRD4 19 116BRD4 4.3 117 BRD4 4.0 119 BRD4 1.2 123 BRD4 11 126 BRD4 3.2 127 BRD4 1.2128 BRD4 16 132 BRD4 13 179 BRD4 2.1 198 BRD4 1.1 215 BRD4 3.8 222 BRD416 256 BRD4 3.8 258 BRD4 0.80 261 BRD4 2.7 262 BRD4 3.3 265 BRD4 5.3 1BRD9 3.0 3 BRD9 3.5 5 BRD9 0.79 6 BRD9 1.5 7 BRD9 0.99 9 BRD9 0.92 11BRD9 5.4 12 BRD9 0.84 18 BRD9 2.1 19 BRD9 0.075 22 BRD9 7.3 33 BRD9 5.434 BRD9 2.2 35 BRD9 11 38 BRD9 8.0 39 BRD9 19 45 BRD9 6.1 85 BRD9 0.5786 BRD9 0.16 87 BRD9 1.0 88 BRD9 1.5 89 BRD9 4.1 90 BRD9 0.30 91 BRD90.20 97 BRD9 0.49 98 BRD9 0.55 102 BRD9 0.86 103 BRD9 0.49 104 BRD9 0.98106 BRD9 0.24 107 BRD9 3.4 108 BRD9 0.20 109 BRD9 0.27 110 BRD9 0.85 111BRD9 0.24 112 BRD9 0.46 114 BRD9 0.073 115 BRD9 0.64 118 BRD9 0.24 120BRD9 0.44 121 BRD9 0.10 122 BRD9 2.2 124 BRD9 2.9 125 BRD9 0.13 129 BRD90.22 131 BRD9 1.6 134 BRD9 0.28 136 BRD9 0.40 138 BRD9 0.31 146 BRD9 1.6159 BRD9 4.3 161 BRD9 2.9 190 BRD9 15 217 BRD9 4.7 248 BRD9 3.3 257 BRD90.18 259 BRD9 0.60 260 BRD9 0.18 263 BRD9 0.48 264 BRD9 0.44 2 CECR2 1421 CECR2 0.89 23 CECR2 2.1 26 CECR2 3.2 29 CECR2 1.8 30 CECR2 3.8 37CECR2 3.1 41 CECR2 0.77 59 CECR2 0.89 60 CECR2 10.3 61 CECR2 1.0 62CECR2 1.5 65 CECR2 1.4 66 CECR2 2.4 67 CECR2 1.8 68 CECR2 3.0 69 CECR20.45 72 CECR2 2.2 73 CECR2 2.5 74 CECR2 5.9 75 CECR2 4.8 76 CECR2 0.3577 CECR2 2.7 78 CECR2 9.9 79 CECR2 5.1 80 CECR2 0.51 113 CECR2 0.31 139CECR2 0.24 140 CECR2 0.34 141 CECR2 0.39 142 CECR2 0.29 143 CECR2 0.40144 CECR2 0.43 145 CECR2 0.41 147 CECR2 0.51 158 CECR2 0.79 160 CECR20.18 162 CECR2 0.12 163 CECR2 0.091 164 CECR2 0.21 165 CECR2 0.087 167CECR2 0.12 168 CECR2 0.042 169 CECR2 0.023 170 CECR2 0.042 172 CECR2 1.0173 CECR2 0.99 174 CECR2 0.59 175 CECR2 0.76 176 CECR2 0.93 177 CECR20.69 178 CECR2 0.74 181 CECR2 0.73 182 CECR2 0.41 183 CECR2 0.49 184CECR2 0.47 185 CECR2 0.91 186 CECR2 0.44 187 CECR2 0.79 188 CECR2 2.0189 CECR2 1.0 191 CECR2 0.59 192 CECR2 1.4 197 CECR2 0.73 201 CECR2 0.99202 CECR2 1.3 203 CECR2 1.1 204 CECR2 1.1 205 CECR2 0.71 206 CECR2 0.37207 CECR2 0.81 208 CECR2 1.2 211 CECR2 2.2 212 CECR2 1.7 213 CECR2 0.71214 CECR2 0.66 216 CECR2 1.2 218 CECR2 0.77 220 CECR2 1.1 221 CECR2 0.67223 CECR2 0.97 224 CECR2 0.78 225 CECR2 1.4 226 CECR2 0.70 227 CECR2 2.0229 CECR2 0.64 230 CECR2 0.79 232 CECR2 1.2 233 CECR2 0.77 234 CECR2 1.0239 CECR2 2.3 241 CECR2 1.1 242 CECR2 1.4 243 CECR2 2.0 244 CECR2 19 249CECR2 4.8 251 CECR2 6.2 253 CECR2 0.98 254 CECR2 0.70 266 CECR2 0.030267 CECR2 0.017 268 CECR2 0.023 269 CECR2 0.033 270 CECR2 0.018 271CECR2 0.011 272 CECR2 0.035 273 CECR2 4.90 274 CECR2 0.074 275 CECR20.11 276 CECR2 0.038 277 CECR2 0.053 278 CECR2 0.057 279 CECR2 0.012 280CECR2 0.049 281 CECR2 0.032 282 CECR2 0.067 283 CECR2 0.044 284 CECR20.053 285 CECR2 0.15 286 CECR2 0.041 287 CECR2 0.084 288 CECR2 0.041 289CECR2 0.045 290 CECR2 0.050 291 CECR2 0.140 4 TAF-1 0.32 10 TAF-1 4.7 14TAF-1 3.7 15 TAF-1 0.97 16 TAF-1 6.0 17 TAF-1 3.6 20 TAF-1 1.5 24 TAF-10.15 25 TAF-1 0.69 27 TAF-1 6.9 36 TAF-1 1.7 40 TAF-1 0.069 42 TAF-10.21 43 TAF-1 0.72 44 TAF-1 0.34 47 TAF-1 2.3 48 TAF-1 1.5 49 TAF-1 3.951 TAF-1 4.4 52 TAF-1 7.1 53 TAF-1 8.2 54 TAF-1 2.9 56 TAF-1 2.5 58TAF-1 1.5 63 TAF-1 4.7 70 TAF-1 6.4 71 TAF-1 3.0 81 TAF-1 0.71 82 TAF-17.0 83 TAF-1 0.67 84 TAF-1 5.7 100 TAF-1 1.7 130 TAF-1 1.2 133 TAF-10.85 135 TAF-1 1.3 137 TAF-1 0.51 148 TAF-1 0.44 149 TAF-1 0.32 150TAF-1 0.36 151 TAF-1 0.55 152 TAF-1 0.57 153 TAF-1 0.49 154 TAF-1 0.53155 TAF-1 0.33 156 TAF-1 0.99 157 TAF-1 1.6 166 TAF-1 2.1 171 TAF-1 0.26180 TAF-1 0.16 193 TAF-1 1.6 199 TAF-1 18 200 TAF-1 8.0 209 TAF-1 0.58210 TAF-1 5.3 219 TAF-1 3.6 228 TAF-1 3.3 231 TAF-1 9.9 235 TAF-1 9.9236 TAF-1 14 238 TAF-1 2.1 240 TAF-1 3.4 250 TAF-1 14 252 TAF-1 5.0 255TAF-1 4.8

While a number of embodiments have been described, these examples may bealtered to provide other embodiments that utilize the compounds andmethods described herein. Therefore, the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of formula (I):

or a salt thereof, wherein: R¹ is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl,C₂₋₁₂alkynyl, or carbocyclyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl,C₂₋₁₂alkynyl, and carbocyclyl of R¹ is optionally substituted with oneor more groups R^(a); R² is H, C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl,or C₃₋₈cycloalkyl, wherein each C₁₋₁₂alkyl, C₂₋₁₂alkenyl, C₂₋₁₂alkynyl,and C₃₋₈cycloalkyl of R² is optionally substituted with one or moregroups R^(b); and each R^(a) is independently selected from oxo,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(v))₂,—S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v), —O—C(O)—R^(v),—O—C(O)—O—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—O—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—OR^(v), —N(R^(v))—C(O)—N(R^(v))₂,—N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v), —N(R^(v))—S(O)₂—R^(v),—N(R^(v))—S(O)—N(R^(v))₂, and —N(R^(v))—S(O)₂—N(R^(v))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, andheterocyclyl, is optionally substituted with one or more groupsindependently selected from oxo, halo, —NO₂, —N(R^(v))₂, —CN,—C(O)—N(R^(v))₂, —S(O)—N(R^(v))₂, —S(O)₂—N(R^(v))₂, —O—R^(v), —S—R^(v),—O—C(O)—R^(v), —C(O)—R^(v), —C(O)—O—R^(v), —S(O)—R^(v), —S(O)₂—R^(v),—C(O)—N(R^(v))₂, —N(R^(v))—C(O)—R^(v), —N(R^(v))—S(O)—R^(v),—N(R^(v))—S(O)₂—R^(v) and C₁₋₆alkyl that is optionally substituted withone or more groups independently selected from oxo and halo; each R^(b)is independently selected from oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂,—N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂, —S(O)₂—N(R^(w))₂,—O—R^(w), —S—R^(w), —O—C(O)—R^(w), —O—C(O)—O—R^(w), —C(O)—R^(w),—C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —O—C(O)—N(R^(w))₂,—N(R^(w))—C(O)—OR^(w), —N(R^(w))—C(O)—N(R^(w))₂, —N(R^(w))—C(O)—R^(w),—N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w), —N(R^(w))—S(O)—N(R^(w))₂,and —N(R^(w))—S(O)₂—N(R^(w))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected from oxo,halo, —NO₂, —N(R^(w))₂, —CN, —C(O)—N(R^(w))₂, —S(O)—N(R^(w))₂,—S(O)₂—N(R^(w))₂, —O—R^(w), —S—R^(w), —O—C(O)—R^(w), —C(O)—R^(w),—C(O)—O—R^(w), —S(O)—R^(w), —S(O)₂—R^(w), —C(O)—N(R^(w))₂,—N(R^(w))—C(O)—R^(w), —N(R^(w))—S(O)—R^(w), —N(R^(w))—S(O)₂—R^(w) andC₁₋₆alkyl that is optionally substituted with one or more groupsindependently selected from oxo and halo; each R^(c) and R^(d) isindependently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups, is optionally substituted with one or moregroups independently selected from oxo, carbocyclyl, heterocyclyl, halo,—NO₂, —N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂,—S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), andC₁₋₆alkyl, which heterocyclyl, carbocyclyl and C₁₋₆alkyl are optionallysubstituted with one or more groups independently selected from oxo,halo, C₁₋₆alkyl, cyano, —O—R^(h), heterocyclyl, and carbocyclyl that isoptionally substituted with one or more groups independently selectedfrom halo, and C₁₋₆alkyl; or R^(c) and R^(d) are taken together with thenitrogen to which they are attached to form a heterocyclyl that isoptionally substituted with one or more groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂,and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more groupsindependently selected from halo and C₁₋₆alkyl; each R^(h) isindependently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected from oxo,halo, amino, hydroxyl, carbocyclyl, heterocyclyl, and C₁-C₆ alkyl thatis optionally substituted with one or more groups independently selectedfrom oxo and halo; or two R^(h) are taken together with the nitrogen towhich they are attached to form a heterocyclyl that is optionallysubstituted with one or more groups independently selected from oxo,halo and C₁-C₃alkyl that is optionally substituted with one or moregroups independently selected from oxo and halo; each R^(v) isindependently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, and heterocyclyl, wherein each C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl is optionallysubstituted with one or more groups independently selected from oxo,halo, amino, hydroxyl, and C₁-C₆ alkyl that is optionally substitutedwith one or more groups independently selected from oxo and halo; or twoR^(v) are taken together with the nitrogen to which they are attached toform a heterocyclyl that is optionally substituted with one or moregroups independently selected from oxo, halo and C₁₋₃alkyl that isoptionally substituted with one or more groups independently selectedfrom oxo and halo; and each R^(w) is independently selected fromhydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, andheterocyclyl, wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,carbocyclyl, and heterocyclyl is optionally substituted with one or moregroups independently selected from oxo, halo, amino, hydroxyl, and C₁-C₆alkyl that is optionally substituted with one or more groupsindependently selected from oxo and halo; or two R^(w) are takentogether with the nitrogen to which they are attached to form aheterocyclyl that is optionally substituted with one or more groupsindependently selected from oxo, halo and C₁₋₃alkyl that is optionallysubstituted with one or more groups independently selected from oxo andhalo.
 2. (canceled)
 3. The compound of claim 1 wherein R¹ is C₁₋₆alkylor C₂₋₆alkenyl, wherein each C₁₋₆alkyl and, C₂₋₆alkenyl is optionallysubstituted with one or more groups R^(a).
 4. (canceled)
 5. The compoundof claim 1 wherein R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein eachC₁₋₆alkyl and C₂₋₆alkenyl is optionally substituted with one or moregroups independently selected from carbocyclyl, —F, —Cl, —O—R^(v),—O—C(O)—R^(v), —C(O)—R^(v), and —C(O)—O—R^(v).
 6. The compound of claim1 wherein R¹ is C₁₋₆alkyl or C₂₋₆alkenyl, wherein each C₁₋₆alkyl andC₂₋₆alkenyl is optionally substituted with one or more groupsindependently selected from C₃₋₆cycloalkyl.
 7. The compound of claim 1wherein R¹ is methyl, butyl, 2-propenyl, 2-buten-1-yl, 3-buten-1-yl or2-cyclopropylethyl.
 8. (canceled)
 9. The compound of claim 1 wherein R²is H or C₁₋₆alkyl wherein each C₁₋₆alkyl is optionally substituted withone or more groups R^(b). 10-13. (canceled)
 14. The compound of claim 1wherein R^(c) is hydrogen, C₁₋₆alkyl, or C₃₋₈cycloalkyl, wherein eachC₁₋₆alkyl and C₃₋₈cycloalkyl is optionally substituted with one or moresubstituent groups independently selected from —O—R^(h).
 15. Thecompound of claim 1 wherein R^(c) is hydrogen, methyl, ethyl,cyclopropyl, cyclobutyl, or 2-methoxyethyl. 16-18. (canceled)
 19. Thecompound of claim 1 wherein R^(d) is C₁₋₆alkyl that is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups is optionally substituted with one or more groupsindependently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h),—S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, whichheterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted withone or more groups independently selected from oxo, halo, C₁₋₆alkyl,cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionallysubstituted with one or more groups independently selected from halo andC₁₋₆alkyl.
 20. The compound of claim 1 wherein R^(d) is carbocyclyl thatis optionally substituted with one or more substituent groupsindependently selected from oxo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN,—C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h),—O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h),—S(O)₂—R^(h), —O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h),—N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h),—N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂, and—N(R^(h))—S(O)₂—N(R^(h))₂, wherein any C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, carbocyclyl, and heterocyclyl of the substituent groups isoptionally substituted with one or more groups independently selectedfrom oxo, carbocyclyl, heterocyclyl, halo, —NO₂, —N(R^(h))₂, —CN,—C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h),—O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h),N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, which heterocyclyl, carbocyclyl andC₁₋₆alkyl are optionally substituted with one or more groupsindependently selected from oxo, halo, C₁₋₆alkyl, cyano, —O—R^(h),heterocyclyl, and carbocyclyl that is optionally substituted with one ormore groups independently selected from halo and C₁₋₆alkyl.
 21. Thecompound of claim 1 wherein R^(d) is heterocyclyl that is optionallysubstituted with one or more substituent groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl ofthe substituent groups is optionally substituted with one or more groupsindependently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —C(O)—R^(h), —C(O)—O—R^(h),—S(O)—R^(h), —S(O)₂—R^(h), —C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), N(R^(h))—S(O)₂—R^(h), and C₁₋₆alkyl, whichheterocyclyl, carbocyclyl and C₁₋₆alkyl are optionally substituted withone or more groups independently selected from oxo, halo, C₁₋₆alkyl,cyano, —O—R^(h), heterocyclyl, and carbocyclyl that is optionallysubstituted with one or more groups independently selected from halo andC₁₋₆alkyl.
 22. (canceled)
 23. The compound of claim 1 wherein R^(c) andR^(d) are taken together with the nitrogen to which they are attached toform a 5-6 membered monocyclic heterocyclyl or a 8-12 membered bicyclicheterocyclyl, wherein the monocyclic or bicyclic heterocyclyl isoptionally substituted with one or more groups independently selectedfrom oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl,heterocyclyl, —F, —Cl, —Br, —I, —NO₂, —N(R^(v))₂, —CN, —C(O)—N(R^(h))₂,—S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂, —O—R^(h), —S—R^(h), —O—C(O)—R^(h),—O—C(O)—O—R^(h), —C(O)—R^(h), —C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h),—O—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—R^(h), —N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h),—N(R^(h))—S(O)—N(R^(h))₂, and —N(R^(h))—S(O)₂—N(R^(h))₂, wherein anyC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, carbocyclyl, and heterocyclyl isoptionally substituted with one or more groups independently selectedfrom C₁₋₆alkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO₂,—N(R^(h))₂, —CN, —C(O)—N(R^(h))₂, —S(O)—N(R^(h))₂, —S(O)₂—N(R^(h))₂,—O—R^(h), —S—R^(h), —O—C(O)—R^(h), —O—C(O)—O—R^(h), —C(O)—R^(h),—C(O)—O—R^(h), —S(O)—R^(h), —S(O)₂—R^(h), —O—C(O)—N(R^(h))₂,—N(R^(h))—C(O)—OR^(h), —N(R^(h))—C(O)—N(R^(h))₂, —N(R^(h))—C(O)—R^(h),—N(R^(h))—S(O)—R^(h), —N(R^(h))—S(O)₂—R^(h), —N(R^(h))—S(O)—N(R^(h))₂,and —N(R^(h))—S(O)₂—N(R^(h))₂, which C₁₋₆alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more groupsindependently selected from halo and C₁₋₆alkyl.
 24. The compound ofclaim 1 wherein —C(═O)NR^(c)R^(d) is selected from:


25. The compound of claim 1 that is selected from the group consistingof:

or a salt thereof.
 26. A composition comprising a compound of formula(I) as described in claim 1 or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable adjuvant, carrier, orvehicle. 27-37. (canceled)
 38. A method of increasing efficacy of acancer treatment comprising a cytotoxic agent in an animal comprisingadministering to the animal an effective amount of a compound of formula(I), a pharmaceutically acceptable salt thereof, or a compositionthereof as described in claim
 1. 39. (canceled)
 40. A method of delayingor preventing development of cancer resistance to a cytotoxic agent inan animal, comprising administering to the animal a compound of formula(I), a pharmaceutically acceptable salt thereof, or a compositionthereof as described in claim
 1. 41. A method of extending the durationof response to a cancer therapy in an animal, comprising administeringto an animal undergoing the cancer therapy a compound of formula (I), apharmaceutically acceptable salt thereof, or a composition thereof asdescribed in claim 1, wherein the duration of response to the cancertherapy when the compound of formula (I) or the pharmaceuticallyacceptable salt thereof is administered is extended over the duration ofresponse to the cancer therapy in the absence of the administration ofthe compound of formula (I) or the pharmaceutically acceptable saltthereof.
 42. A method of treating cancer in an individual comprisingadministering to the individual (a) a compound of formula (I), apharmaceutically acceptable salt thereof, or a composition thereof asdescribed in claim 1, and (b) a cytotoxic agent. 43-52. (canceled)